NCRCRG-CN-iSearch_-_Publications-export_2022-06-28-19-52-25.tsv

Grant Number	Group	Modality			Other accessions	GEO accession	OMERO accession	dbGaP accession number	PRIDE accession	DOI	PMID	Pub Year	Title	Abstract	MeSH Keywords	MeSH Extracted	PubMed Keywords	Authors	Author Affiliation	RCR	Total Citations	Journal Name	Journal Volume	Journal Issue	Journal Pages
U19MH104172	Group 1									10.1016/j.stem.2015.07.017	26279266	2015	Human Neuropsychiatric Disease Modeling using Conditional Deletion Reveals Synaptic Transmission Defects Caused by Heterozygous Mutations in NRXN1.	Heterozygous mutations of the NRXN1 gene, which encodes the presynaptic cell-adhesion molecule neurexin-1, were repeatedly associated with autism and schizophrenia. However, diverse clinical presentations of NRXN1 mutations in patients raise the question of whether heterozygous NRXN1 mutations alone directly impair synaptic function. To address this question under conditions that precisely control for genetic background, we generated human ESCs with different heterozygous conditional NRXN1 mutations and analyzed two different types of isogenic control and NRXN1 mutant neurons derived from these ESCs. Both heterozygous NRXN1 mutations selectively impaired neurotransmitter release in human neurons without changing neuronal differentiation or synapse formation. Moreover, both NRXN1 mutations increased the levels of CASK, a critical synaptic scaffolding protein that binds to neurexin-1. Our results show that, unexpectedly, heterozygous inactivation of NRXN1 directly impairs synaptic function in human neurons, and they illustrate the value of this conditional deletion approach for studying the functional effects of disease-associated mutations.	Amino Acid Sequence;Calcium-Binding Proteins;Cell Adhesion Molecules, Neuronal;Cell Differentiation;Cell Membrane;Enzyme Stability;Gene Knockout Techniques;Gene Targeting;Guanylate Kinases;Heterozygote;Human Embryonic Stem Cells;Humans;Mental Disorders;Miniature Postsynaptic Potentials;Models, Biological;Molecular Sequence Data;Mutation;Nerve Tissue Proteins;Neural Cell Adhesion Molecules;Neurons;Neurotransmitter Agents;Phenotype;Synapses;Synaptic Transmission;Synaptic Vesicles	Address;Amino Acid Sequence;Autistic Disorder;Calcium-Binding Proteins;Cell Adhesion;Cell Adhesion Molecules;Cell Adhesion Molecules, Neuronal;Cell Differentiation;Cell Membrane;Cells;Disease;Enzyme Stability;Gene Knockout Techniques;Gene Targeting;Genes;Genetic Background;Guanylate Kinases;Heterozygote;Human Embryonic Stem Cells;Humans;Mental Disorders;Miniature Postsynaptic Potentials;Models, Biological;Molecular Sequence Data;Mutation;Nerve Tissue Proteins;Neural Cell Adhesion Molecules;Neurons;Neurotransmitter Agents;Neurotransmitters;Patients;Phenotype;Proteins;Schizophrenia;Synapses;Synaptic Transmission;Synaptic Vesicles	autism;human neurons;iN cells;neurexin;schizophrenia;synapse;synaptic cell adhesion	Pak, ChangHui;Danko, Tamas;Zhang, Yingsha;Aoto, Jason;Anderson, Garret;Maxeiner, Stephan;Yi, Fei;Wernig, Marius;Südhof, Thomas C	[Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine]	4.43	126	Cell stem cell	17	3	316-28
U19MH104172	Group 1									10.1126/science.aaf2669	26966193	2016	Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.	Heterozygous SHANK3 mutations are associated with idiopathic autism and Phelan-McDermid syndrome. SHANK3 is a ubiquitously expressed scaffolding protein that is enriched in postsynaptic excitatory synapses. Here, we used engineered conditional mutations in human neurons and found that heterozygous and homozygous SHANK3 mutations severely and specifically impaired hyperpolarization-activated cation (Ih) channels. SHANK3 mutations caused alterations in neuronal morphology and synaptic connectivity; chronic pharmacological blockage of Ih channels reproduced these phenotypes, suggesting that they may be secondary to Ih-channel impairment. Moreover, mouse Shank3-deficient neurons also exhibited severe decreases in Ih currents. SHANK3 protein interacted with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) that form Ih channels, indicating that SHANK3 functions to organize HCN channels. Our data suggest that SHANK3 mutations predispose to autism, at least partially, by inducing an Ih channelopathy that may be amenable to pharmacological intervention.	Action Potentials;Animals;Autism Spectrum Disorder;Cells, Cultured;Channelopathies;Chromosome Deletion;Chromosome Disorders;Chromosomes, Human, Pair 22;Embryonic Stem Cells;Gene Deletion;Genetic Engineering;Genetic Predisposition to Disease;Haploinsufficiency;Humans;Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels;Mice;Mice, Knockout;Microfilament Proteins;Mutagenesis;Nerve Tissue Proteins;Neurons;Synapses;Synaptic Transmission;Telomeric 22q13 Monosomy Syndrome	Action Potentials;Animals;Autism Spectrum Disorder;Autistic Disorder;Cations;Cells, Cultured;Channelopathies;Chromosome Deletion;Chromosome Disorders;Chromosomes, Human, Pair 22;Embryonic Stem Cells;Form;Gene Deletion;Genetic Engineering;Genetic Predisposition to Disease;Haploinsufficiency;Humans;Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels;Mice;Mice, Knockout;Microfilament Proteins;Monosomy;Mutagenesis;Mutation;Nerve Tissue Proteins;Neurons;Phenotype;Proteins;Synapses;Synaptic Transmission;Syndrome		Yi, Fei;Danko, Tamas;Botelho, Salome Calado;Patzke, Christopher;Pak, ChangHui;Wernig, Marius;Südhof, Thomas C	[Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine]	7.16	165	Science (New York, N.Y.)	352	6286	aaf2669
U19MH104172	Group 1	Imaging								10.1073/pnas.1621321114	28154140	2017	Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand.	Establishment, specification, and validation of synaptic connections are thought to be mediated by interactions between pre- and postsynaptic cell-adhesion molecules. Arguably, the best-characterized transsynaptic interactions are formed by presynaptic neurexins, which bind to diverse postsynaptic ligands. In a proteomic screen of neurexin-1 (Nrxn1) complexes immunoisolated from mouse brain, we identified carbonic anhydrase-related proteins CA10 and CA11, two homologous, secreted glycoproteins of unknown function that are predominantly expressed in brain. We found that CA10 directly binds in a cis configuration to a conserved membrane-proximal, extracellular sequence of α- and β-neurexins. The CA10-neurexin complex is stable and stoichiometric, and results in formation of intermolecular disulfide bonds between conserved cysteine residues in neurexins and CA10. CA10 promotes surface expression of α- and β-neurexins, suggesting that CA10 may form a complex with neurexins in the secretory pathway that facilitates surface transport of neurexins. Moreover, we observed that the Nrxn1 gene expresses from an internal 3' promoter a third isoform, Nrxn1γ, that lacks all Nrxn1 extracellular domains except for the membrane-proximal sequences and that also tightly binds to CA10. Our data expand the understanding of neurexin-based transsynaptic interaction networks by providing further insight into the interactions nucleated by neurexins at the synapse.	Amino Acid Sequence;Animals;Brain;Calcium-Binding Proteins;Conserved Sequence;HEK293 Cells;Humans;Ligands;Mice;Nerve Tissue Proteins;Neural Cell Adhesion Molecules;Neurons	Amino Acid Sequence;Animals;Automobiles;Brain;Calcium-Binding Proteins;Carbonic Anhydrases;Cell Adhesion;Cell Adhesion Molecules;Comprehension;Conserved Sequence;Cysteine;Disulfides;Form;Genes;Glycoproteins;HEK293 Cells;Humans;Ligands;Membranes;Mice;Nerve Tissue Proteins;Neural Cell Adhesion Molecules;Neurons;Protein Isoforms;Proteins;Proteomics;Secretory Pathway;Synapses;Thought	Car10;Car11;cell adhesion;synapse	Sterky, Fredrik H;Trotter, Justin H;Lee, Sung-Jin;Recktenwald, Christian V;Du, Xiao;Zhou, Bo;Zhou, Peng;Schwenk, Jochen;Fakler, Bernd;Südhof, Thomas C	[Stanford University, Stanford University School of Medicine, University of Gothenburg];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[University of Gothenburg];[Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine];[University of Freiburg];[University of Freiburg];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine, University of Gothenburg]	1.78	39	Proceedings of the National Academy of Sciences of the United States of America	114	7	E1253-E1262
U19MH104172	Group 1	Imaging								10.1016/j.neuron.2017.04.011	28472659	2017	Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins.	Neurexins are recognized as key organizers of synapses that are essential for normal brain function. However, it is unclear whether neurexins are fundamental building blocks of all synapses with similar overall functions or context-dependent specifiers of synapse properties. To address this question, we produced triple cKO (conditional knockout) mice that allow ablating all neurexin expression in mice. Using neuron-specific manipulations combined with immunocytochemistry, paired recordings, and two-photon Ca2+ imaging, we analyzed excitatory synapses formed by climbing fibers on Purkinje cells in cerebellum and inhibitory synapses formed by parvalbumin- or somatostatin-positive interneurons on pyramidal layer 5 neurons in the medial prefrontal cortex. After pan-neurexin deletions, we observed in these synapses severe but dramatically different synaptic phenotypes that ranged from major impairments in their distribution and function (climbing-fiber synapses) to large decreases in synapse numbers (parvalbumin-positive synapses) and severe alterations in action potential-induced presynaptic Ca2+ transients (somatostatin-positive synapses). Thus, neurexins function primarily as context-dependent specifiers of synapses.	Action Potentials;Animals;Axons;Calcium;Calcium-Binding Proteins;Cerebellum;Gene Expression Profiling;Immunohistochemistry;Interneurons;Mice;Mice, Knockout;Nerve Tissue Proteins;Neural Cell Adhesion Molecules;Neurons;Optical Imaging;Parvalbumins;Patch-Clamp Techniques;Prefrontal Cortex;Purkinje Cells;Single-Cell Analysis;Somatostatin;Synapses	Action Potentials;Address;Animals;Autistic Disorder;Axons;Brain;Calcium;Calcium-Binding Proteins;Cell Adhesion Molecules;Cerebellum;Gene Expression Profiling;Immunocytochemistry;Immunohistochemistry;Interneurons;Mice;Mice, Knockout;Nerve Tissue Proteins;Neural Cell Adhesion Molecules;Neurons;Optical Imaging;Overall;Parvalbumins;Patch-Clamp Techniques;Phenotype;Photons;Prefrontal Cortex;Probability;Purkinje Cells;Schizophrenia;Single-Cell Analysis;Somatostatin;Synapses;Transients	autism;cell-adhesion molecule;cerebellum;interneuron;neurexin;neuroligin;release probability;schizophrenia;synapse;synaptogenesis	Chen, Lulu Y;Jiang, Man;Zhang, Bo;Gokce, Ozgun;Südhof, Thomas C	[Howard Hughes Medical Institute, Stanford University];[Howard Hughes Medical Institute, Stanford University];[Howard Hughes Medical Institute, Stanford University];[Howard Hughes Medical Institute, Stanford University];[Howard Hughes Medical Institute, Stanford University]	4.06	93	Neuron	94	3	611-625.e4
U19MH104172	Group 1	Genomics				GSE97710				10.1038/nmeth.4291	28504679	2017	Generation of pure GABAergic neurons by transcription factor programming.	Approaches to differentiating pluripotent stem cells (PSCs) into neurons currently face two major challenges-(i) generated cells are immature, with limited functional properties; and (ii) cultures exhibit heterogeneous neuronal subtypes and maturation stages. Using lineage-determining transcription factors, we previously developed a single-step method to generate glutamatergic neurons from human PSCs. Here, we show that transient expression of the transcription factors Ascl1 and Dlx2 (AD) induces the generation of exclusively GABAergic neurons from human PSCs with a high degree of synaptic maturation. These AD-induced neuronal (iN) cells represent largely nonoverlapping populations of GABAergic neurons that express various subtype-specific markers. We further used AD-iN cells to establish that human collybistin, the loss of gene function of which causes severe encephalopathy, is required for inhibitory synaptic function. The generation of defined populations of functionally mature human GABAergic neurons represents an important step toward enabling the study of diseases affecting inhibitory synaptic transmission.	Animals;Basic Helix-Loop-Helix Transcription Factors;Cell Differentiation;Cell Engineering;Cells, Cultured;GABAergic Neurons;Homeodomain Proteins;Humans;Mice;Pluripotent Stem Cells;Transcription Factors	Animals;Basic Helix-Loop-Helix Transcription Factors;Cell Differentiation;Cell Engineering;Cells;Cells, Cultured;Culture;Disease;Encephalopathy;Exhibition;Face;GABAergic Neurons;Generations;Genes;Homeodomain Proteins;Humans;Methods;Mice;Neurons;Pluripotent Stem Cells;Population;Synaptic Transmission;Transcription Factors;Transients		Yang, Nan;Chanda, Soham;Marro, Samuele;Ng, Yi-Han;Janas, Justyna A;Haag, Daniel;Ang, Cheen Euong;Tang, Yunshuo;Flores, Quetzal;Mall, Moritz;Wapinski, Orly;Li, Mavis;Ahlenius, Henrik;Rubenstein, John L;Chang, Howard Y;Buylla, Arturo Alvarez;Südhof, Thomas C;Wernig, Marius	[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine];[University of California, San Francisco];[University of California, San Francisco];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine];[Stanford University School of Medicine];[Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine];[University of California, San Francisco];[Stanford University School of Medicine];[University of California, San Francisco];[Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine]	6.98	153	Nature methods	14	6	621-628
U19MH104172	Group 1									10.1523/ENEURO.0219-17.2017	29218324	2017	Intellicount: High-Throughput Quantification of Fluorescent Synaptic Protein Puncta by Machine Learning.	Synapse formation analyses can be performed by imaging and quantifying fluorescent signals of synaptic markers. Traditionally, these analyses are done using simple or multiple thresholding and segmentation approaches or by labor-intensive manual analysis by a human observer. Here, we describe Intellicount, a high-throughput, fully-automated synapse quantification program which applies a novel machine learning (ML)-based image processing algorithm to systematically improve region of interest (ROI) identification over simple thresholding techniques. Through processing large datasets from both human and mouse neurons, we demonstrate that this approach allows image processing to proceed independently of carefully set thresholds, thus reducing the need for human intervention. As a result, this method can efficiently and accurately process large image datasets with minimal interaction by the experimenter, making it less prone to bias and less liable to human error. Furthermore, Intellicount is integrated into an intuitive graphical user interface (GUI) that provides a set of valuable features, including automated and multifunctional figure generation, routine statistical analyses, and the ability to run full datasets through nested folders, greatly expediting the data analysis process.	Algorithms;Animals;Cells, Cultured;High-Throughput Screening Assays;Humans;Image Processing, Computer-Assisted;Machine Learning;Mice;Software;Synapses	Ability;Algorithms;Animals;Bias;Cells, Cultured;Data Analysis;Dataset;Generations;High-Throughput Screening Assays;Humans;Image Processing, Computer-Assisted;Immunofluorescence;Machine Learning;Methods;Mice;Needs;Neurons;Program;Proteins;Software;Synapses	automated image analysis;high-throughput;immunofluorescence;machine learning;synapse formation;synapse quantification	Fantuzzo, J A;Mirabella, V R;Hamod, A H;Hart, R P;Zahn, J D;Pang, Z P	[Rutgers University];[Rutgers University];;[Rutgers University];[Rutgers University];[Robert Wood Johnson Medical School, Rutgers University, Rutgers University, New Brunswick]	0.78	18	eNeuro	4	6
U19MH104172	Group 1									10.1016/j.cell.2017.10.024	29100073	2017	Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits.	Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here, we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, especially schizophrenia, autism, and Tourette syndrome. Thus, neurexins nucleate an overall trans-synaptic signaling network that controls synapse properties, which thereby determines the precise responses of synapses to spike patterns in a neuron and circuit and which is vulnerable to impairments in neuropsychiatric disorders.	Alternative Splicing;Animals;Autistic Disorder;Cell Adhesion Molecules, Neuronal;Humans;Membrane Glycoproteins;Neural Pathways;Protein Isoforms;Schizophrenia;Signal Transduction;Synapses;Tourette Syndrome	Alternative Splicing;Animals;Autistic Disorder;Brain;Cell Adhesion Molecules, Neuronal;Genes;Humans;Ligands;Logic;Membrane Glycoproteins;Mutation;Neural Pathways;Neurons;Overall;Protein Isoforms;Schizophrenia;Signal Transduction;Synapses;Tourette Syndrome		Südhof, Thomas C	Howard Hughes Medical Institute;Stanford University	14.56	311	Cell	171	4	745-769
U19MH104172	Group 1									10.1126/scitranslmed.aar4338	30068571	2018	The fragile X mutation impairs homeostatic plasticity in human neurons by blocking synaptic retinoic acid signaling.	Fragile X syndrome (FXS) is an X chromosome-linked disease leading to severe intellectual disabilities. FXS is caused by inactivation of the fragile X mental retardation 1 (FMR1) gene, but how FMR1 inactivation induces FXS remains unclear. Using human neurons generated from control and FXS patient-derived induced pluripotent stem (iPS) cells or from embryonic stem cells carrying conditional FMR1 mutations, we show here that loss of FMR1 function specifically abolished homeostatic synaptic plasticity without affecting basal synaptic transmission. We demonstrated that, in human neurons, homeostatic plasticity induced by synaptic silencing was mediated by retinoic acid, which regulated both excitatory and inhibitory synaptic strength. FMR1 inactivation impaired homeostatic plasticity by blocking retinoic acid-mediated regulation of synaptic strength. Repairing the genetic mutation in the FMR1 gene in an FXS patient cell line restored fragile X mental retardation protein (FMRP) expression and fully rescued synaptic retinoic acid signaling. Thus, our study reveals a robust functional impairment caused by FMR1 mutations that might contribute to neuronal dysfunction in FXS. In addition, our results suggest that FXS patient iPS cell-derived neurons might be useful for studying the mechanisms mediating functional abnormalities in FXS.	Alleles;Animals;Base Sequence;Cell Differentiation;Cell Line;Embryonic Stem Cells;Excitatory Postsynaptic Potentials;Fragile X Mental Retardation Protein;Fragile X Syndrome;Homeostasis;Humans;Mice;Mutation;Neuronal Plasticity;Neurons;Signal Transduction;Synapses;Tretinoin;Trinucleotide Repeats;Up-Regulation	Alleles;Animals;Base Sequence;Carrying;Cell Differentiation;Cell Line;Cells;Disease;Embryonic Stem Cells;Excitatory Postsynaptic Potentials;Fragile X Mental Retardation Protein;Fragile X Syndrome;Genes;Genetics;Homeostasis;Humans;Intellectual Disability;Mediating;Mice;Microscopy, Electron, Scanning Transmission;Mutation;Neuronal Plasticity;Neurons;Patients;Regulation;Signal Transduction;Synapses;Synaptic Transmission;Tretinoin;Trinucleotide Repeats;Up-Regulation;X Chromosome		Zhang, Zhenjie;Marro, Samuele G;Zhang, Yingsha;Arendt, Kristin L;Patzke, Christopher;Zhou, Bo;Fair, Tyler;Yang, Nan;Südhof, Thomas C;Wernig, Marius;Chen, Lu	[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine]	2.07	37	Science translational medicine	10	452
U19MH104172	Group 1									10.1016/j.neuron.2018.09.040	30359597	2018	Towards an Understanding of Synapse Formation.	Synapses are intercellular junctions specialized for fast, point-to-point information transfer from a presynaptic neuron to a postsynaptic cell. At a synapse, a presynaptic terminal secretes neurotransmitters via a canonical release machinery, while a postsynaptic specialization senses neurotransmitters via diverse receptors. Synaptic junctions are likely organized by trans-synaptic cell-adhesion molecules (CAMs) that bidirectionally orchestrate synapse formation, restructuring, and elimination. Many candidate synaptic CAMs were described, but which CAMs are central actors and which are bystanders remains unclear. Moreover, multiple genes encoding synaptic CAMs were linked to neuropsychiatric disorders, but the mechanisms involved are unresolved. Here, I propose that engagement of multifarious synaptic CAMs produces parallel trans-synaptic signals that mediate the establishment, organization, and plasticity of synapses, thereby controlling information processing by neural circuits. Among others, this hypothesis implies that synapse formation can be understood in terms of inter- and intracellular signaling, and that neuropsychiatric disorders involve an impairment in such signaling.	Animals;Brain;Cell Adhesion Molecules;Humans;Neurogenesis;Neuronal Plasticity;Signal Transduction;Synapses	Animals;Brain;Cell Adhesion Molecules;Cells;Comprehension;Genes;Humans;Information Processing;Intercellular Junctions;Neurogenesis;Neuronal Plasticity;Neurons;Neurotransmitters;Organizations;Presynaptic Terminals;Signal Transduction;Specialization;Synapses;Synaptic Receptors	BAIs;cell-adhesion molecules;cerebellins;latrophilins;neurexins;neuroligins;synapse;synaptic plasticity;synaptogenesis;teneurins	Südhof, Thomas C	Howard Hughes Medical Institute;Stanford University;Stanford University School of Medicine	12.32	215	Neuron	100	2	276-293
U19MH104172	Group 1	Genomics				GSE113804				10.1073/pnas.1720273115	29866841	2018	Transdifferentiation of human adult peripheral blood T cells into neurons.	Human cell models for disease based on induced pluripotent stem (iPS) cells have proven to be powerful new assets for investigating disease mechanisms. New insights have been obtained studying single mutations using isogenic controls generated by gene targeting. Modeling complex, multigenetic traits using patient-derived iPS cells is much more challenging due to line-to-line variability and technical limitations of scaling to dozens or more patients. Induced neuronal (iN) cells reprogrammed directly from dermal fibroblasts or urinary epithelia could be obtained from many donors, but such donor cells are heterogeneous, show interindividual variability, and must be extensively expanded, which can introduce random mutations. Moreover, derivation of dermal fibroblasts requires invasive biopsies. Here we show that human adult peripheral blood mononuclear cells, as well as defined purified T lymphocytes, can be directly converted into fully functional iN cells, demonstrating that terminally differentiated human cells can be efficiently transdifferentiated into a distantly related lineage. T cell-derived iN cells, generated by nonintegrating gene delivery, showed stereotypical neuronal morphologies and expressed multiple pan-neuronal markers, fired action potentials, and were able to form functional synapses. These cells were stable in the absence of exogenous reprogramming factors. Small molecule addition and optimized culture systems have yielded conversion efficiencies of up to 6.2%, resulting in the generation of >50,000 iN cells from 1 mL of peripheral blood in a single step without the need for initial expansion. Thus, our method allows the generation of sufficient neurons for experimental interrogation from a defined, homogeneous, and readily accessible donor cell population.	Adolescent;Adult;Aged;Cell Differentiation;Cell Transdifferentiation;Cellular Reprogramming;Female;Fibroblasts;Humans;Induced Pluripotent Stem Cells;Leukocytes, Mononuclear;Male;Middle Aged;Neurons;T-Lymphocytes;Young Adult	Action Potentials;Adolescent;Adult;Aged;Biopsy;Blood;Cell Differentiation;Cell Transdifferentiation;Cells;Cellular Reprogramming;Culture;Disease;Donors;Efficiency;Female;Fibroblasts;Form;Gene Targeting;Generations;Genes;Humans;Induced Pluripotent Stem Cells;Leukocytes, Mononuclear;Male;Methods;Microscopy, Electron, Scanning Transmission;Middle Aged;Mutation;Needs;Neurons;News;Patients;Peripheral Blood Mononuclear Cells;Population;Synapses;T-Lymphocytes;Young Adult	direct conversion;disease modeling;iN cells;induced neuronal cells;transdifferentiation	Tanabe, Koji;Ang, Cheen Euong;Chanda, Soham;Olmos, Victor Hipolito;Haag, Daniel;Levinson, Douglas F;Südhof, Thomas C;Wernig, Marius	[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University];[Howard Hughes Medical Institute, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University];[Stanford University];[Howard Hughes Medical Institute, Stanford University];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University]	2.28	43	Proceedings of the National Academy of Sciences of the United States of America	115	25	6470-6475
U19MH104172	Group 1									10.1016/j.neuron.2019.03.032	31005376	2019	Alternative Splicing of Presynaptic Neurexins Differentially Controls Postsynaptic NMDA and AMPA Receptor Responses.	AMPA- and NMDA-type glutamate receptors mediate distinct postsynaptic signals that differ characteristically among synapses. How postsynaptic AMPA- and NMDA-receptor levels are regulated, however, remains unclear. Using newly generated conditional knockin mice that enable genetic control of neurexin alternative splicing, we show that in hippocampal synapses, alternative splicing of presynaptic neurexin-1 at splice site 4 (SS4) dramatically enhanced postsynaptic NMDA-receptor-mediated, but not AMPA-receptor-mediated, synaptic responses without altering synapse density. In contrast, alternative splicing of neurexin-3 at SS4 suppressed AMPA-receptor-mediated, but not NMDA-receptor-mediated, synaptic responses, while alternative splicing of neurexin-2 at SS4 had no effect on NMDA- or AMPA-receptor-mediated responses. Presynaptic overexpression of the neurexin-1β and neurexin-3β SS4+ splice variants, but not of their SS4- splice variants, replicated the respective SS4+ knockin phenotypes. Thus, different neurexins perform distinct nonoverlapping functions at hippocampal synapses that are independently regulated by alternative splicing. These functions transsynaptically control NMDA and AMPA receptors, thereby mediating presynaptic control of postsynaptic responses.	Alternative Splicing;Animals;Calcium-Binding Proteins;Gene Knock-In Techniques;Hippocampus;Mice;Nerve Tissue Proteins;Neural Cell Adhesion Molecules;RNA Splice Sites;Receptors, AMPA;Receptors, N-Methyl-D-Aspartate;Synapses	Alternative Splicing;Animals;Calcium-Binding Proteins;Epigenetics;Gene Knock-In Techniques;Genetics;Hippocampus;Long-Term Potentiation;Mediating;Memory;Mice;N-Methylaspartate;Nerve Tissue Proteins;Neural Cell Adhesion Molecules;Phenotype;RNA Splice Sites;Receptors, AMPA;Receptors, Glutamate;Receptors, N-Methyl-D-Aspartate;Schizophrenia;Subiculum;Synapses;Synaptic Transmission;alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid	AMPA receptor;NMDA receptor;alternative splicing;epigenetics;long-term potentiation;memory;neurexins;neuroligin;schizophrenia;subiculum;synapse formation;synaptic transmission	Dai, Jinye;Aoto, Jason;Südhof, Thomas C	[Howard Hughes Medical Institute, Stanford University];[Stanford University];[Howard Hughes Medical Institute, Stanford University]	3.41	48	Neuron	102	5	993-1008.e5
U19MH104172	Group 1					GSE129241				10.1016/j.stem.2019.04.021	31155484	2019	Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity.	Human pluripotent stem cells can be rapidly converted into functional neurons by ectopic expression of proneural transcription factors. Here we show that directly reprogrammed neurons, despite their rapid maturation kinetics, can model teratogenic mechanisms that specifically affect early neurodevelopment. We delineated distinct phases of in vitro maturation during reprogramming of human neurons and assessed the cellular phenotypes of valproic acid (VPA), a teratogenic drug. VPA exposure caused chronic impairment of dendritic morphology and functional properties of developing neurons, but not those of mature neurons. These pathogenic effects were associated with VPA-mediated inhibition of the histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) pathways, which caused transcriptional downregulation of many genes, including MARCKSL1, an actin-stabilizing protein essential for dendritic morphogenesis and synapse maturation during early neurodevelopment. Our findings identify a developmentally restricted pathogenic mechanism of VPA and establish the use of reprogrammed neurons as an effective platform for modeling teratogenic pathways.	Animals;Calmodulin-Binding Proteins;Carcinogenesis;Cells, Cultured;Cellular Reprogramming;Electrical Synapses;Glycogen Synthase Kinase 3;Histone Deacetylases;Humans;Mice;Microfilament Proteins;Neurogenesis;Neurons;Pluripotent Stem Cells;Signal Transduction;Teratoma;Valproic Acid	Actins;Affect;Animals;Autistic Disorder;Calmodulin-Binding Proteins;Carcinogenesis;Cells, Cultured;Cellular Reprogramming;Down-Regulation;Ectopic Gene Expression;Electrical Synapses;Gene Expression;Genes;Glycogen Synthase Kinase 3;Histone Deacetylases;Humans;In Vitro;Kinetics;Mice;Microfilament Proteins;Morphogenesis;Neurogenesis;Neurons;Pharmaceutical Preparations;Phenotype;Pluripotent Stem Cells;Proteins;Signal Transduction;Spinal Dysraphism;Synapses;Teratoma;Transcription Factors;Valproic Acid	MARCKSL1;anti-epileptic drug;autism;cellular reprogramming;gene expression;human neurons;neurodevelopment;spina bifida;valproic acid	Chanda, Soham;Ang, Cheen Euong;Lee, Qian Yi;Ghebrial, Michael;Haag, Daniel;Shibuya, Yohei;Wernig, Marius;Südhof, Thomas C	[Colorado State University, Howard Hughes Medical Institute, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine]	1.10	16	Cell stem cell	25	1	103-119.e6
U19MH104172	Group 1									10.1016/j.neuron.2019.05.043	31257103	2019	Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons.	The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human embryonic stem cell-derived neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change-of-function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting that human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.	Animals;Autistic Disorder;Cell Adhesion Molecules, Neuronal;Cells, Cultured;Cerebral Cortex;Embryonic Stem Cells;Excitatory Postsynaptic Potentials;Genes, Reporter;Glutamic Acid;Humans;Mice;Miniature Postsynaptic Potentials;Mutation, Missense;Neurogenesis;Neurons;Phenotype;Receptors, Glutamate;Species Specificity;Synapses;Synaptic Transmission	Affect;Animals;Autistic Disorder;Biological Processes;Carrying;Cell Adhesion Molecules, Neuronal;Cell Line;Cells;Cells, Cultured;Cerebral Cortex;Embryonic Stem Cells;Excitatory Postsynaptic Potentials;Genes;Genes, Reporter;Genetics;Glutamic Acid;Human Embryonic Stem Cells;Humans;Mice;Miniature Postsynaptic Potentials;Mutation;Mutation, Missense;Neurogenesis;Neurons;Phenotype;Receptors, Glutamate;Role;Species Specificity;Synapses;Synaptic Transmission;Work	ASD;Neuroligin-4;autism;embryonic stem cells;induced neuronal (iN) cells;isogenic cell lines;synaptic transmission	Marro, Samuele G;Chanda, Soham;Yang, Nan;Janas, Justyna A;Valperga, Giulio;Trotter, Justin;Zhou, Bo;Merrill, Sean;Yousif, Issa;Shelby, Hannah;Vogel, Hannes;Kalani, M Yashar S;Südhof, Thomas C;Wernig, Marius	[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Stanford University, Stanford University School of Medicine];[University of Virginia School of Medicine];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School]	2.37	34	Neuron	103	4	617-626.e6
U19MH104172	Group 1									10.1016/j.devcel.2019.03.001	30930166	2019	The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution.	Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.	Embryonic Development;Gene Expression Profiling;Gene Expression Regulation, Developmental;Gene Regulatory Networks;Humans;Pediatrics;Single-Cell Analysis;Tissue Distribution	Adult;Atlas;Cells;Complement System Proteins;Comprehension;Critical Pathways;Disease;Embryonic Development;Gene Expression;Gene Expression Profiling;Gene Expression Regulation, Developmental;Gene Regulatory Networks;Genetics;Growth;Health;Human Development;Humans;Life Span;Morphogenesis;Pediatrics;Single-Cell Analysis;Tissue Distribution;Tissues		Taylor, Deanne M;Aronow, Bruce J;Tan, Kai;Bernt, Kathrin;Salomonis, Nathan;Greene, Casey S;Frolova, Alina;Henrickson, Sarah E;Wells, Andrew;Pei, Liming;Jaiswal, Jyoti K;Whitsett, Jeffrey;Hamilton, Kathryn E;MacParland, Sonya A;Kelsen, Judith;Heuckeroth, Robert O;Potter, S Steven;Vella, Laura A;Terry, Natalie A;Ghanem, Louis R;Kennedy, Benjamin C;Helbig, Ingo;Sullivan, Kathleen E;Castelo-Soccio, Leslie;Kreigstein, Arnold;Herse, Florian;Nawijn, Martijn C;Koppelman, Gerard H;Haendel, Melissa;Harris, Nomi L;Rokita, Jo Lynne;Zhang, Yuanchao;Regev, Aviv;Rozenblatt-Rosen, Orit;Rood, Jennifer E;Tickle, Timothy L;Vento-Tormo, Roser;Alimohamed, Saif;Lek, Monkol;Mar, Jessica C;Loomes, Kathleen M;Barrett, David M;Uapinyoying, Prech;Beggs, Alan H;Agrawal, Pankaj B;Chen, Yi-Wen;Muir, Amanda B;Garmire, Lana X;Snapper, Scott B;Nazarian, Javad;Seeholzer, Steven H;Fazelinia, Hossein;Singh, Larry N;Faryabi, Robert B;Raman, Pichai;Dawany, Noor;Xie, Hongbo Michael;Devkota, Batsal;Diskin, Sharon J;Anderson, Stewart A;Rappaport, Eric F;Peranteau, William;Wikenheiser-Brokamp, Kathryn A;Teichmann, Sarah;Wallace, Douglas;Peng, Tao;Ding, Yang-Yang;Kim, Man S;Xing, Yi;Kong, Sek Won;Bönnemann, Carsten G;Mandl, Kenneth D;White, Peter S	[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine];[Alex's Lemonade Stand Foundation, Perelman School of Medicine, Translational Therapeutics, Inc, University of Pennsylvania];;[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's National Medical Center, George Washington University];[Cincinnati Children's Hospital Medical Center];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Toronto General Hospital, University of Toronto];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, Translational Therapeutics, Inc, University of Pennsylvania];[Cincinnati Children's Hospital Medical Center];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, University of Pennsylvania];[University of California, San Francisco];;[Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen];[Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen];[Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Oregon State University];[Lawrence Berkeley National Laboratory];[Children's Hospital of Philadelphia];[Children's Hospital of Philadelphia, Rutgers University];[Broad Institute of MIT and Harvard, Howard Hughes Medical Institute, Massachusetts Institute of Technology];[Broad Institute of MIT and Harvard];[Broad Institute of MIT and Harvard];[Broad Institute of MIT and Harvard];[Wellcome Sanger Institute, Wellcome Trust];[Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine];[Yale School of Medicine];[University of Queensland];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's National Medical Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health];[Boston Children's Hospital, Harvard Medical School];[Boston Children's Hospital, Harvard Medical School];[Children's National Medical Center, George Washington University];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[University of Michigan Medical School, University of Michigan, Ann Arbor];[Boston Children's Hospital, Harvard Medical School];[Children's National Medical Center, George Washington University];[Children's Hospital of Philadelphia];[Children's Hospital of Philadelphia];[Children's Hospital of Philadelphia];[Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia];[Children's Hospital of Philadelphia];[Children's Hospital of Philadelphia];[Children's Hospital of Philadelphia];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia];[Children's Hospital of Philadelphia];[Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine];[EMBL-EBI Hinxton, European Molecular Biology Laboratory, Wellcome Sanger Institute, Wellcome Trust];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Children's Hospital of Philadelphia];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[Boston Children's Hospital, Harvard Medical School];[George Washington University, National Institute of Neurological Disorders and Stroke, National Institutes of Health];[Boston Children's Hospital, Harvard Medical School];[Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine]	2.10	31	Developmental cell	49	1	10-29
U19MH104172	Group 1									10.1016/j.jneumeth.2020.109041	33340555	2021	A simple Ca2+-imaging approach to neural network analyses in cultured neurons.	Ca2+-imaging is a powerful tool to measure neuronal dynamics and network activity. To monitor network-level changes in cultured neurons, neuronal activity is often evoked by electrical or optogenetic stimulation and assessed using multi-electrode arrays or sophisticated imaging. Although such approaches allow detailed network analyses, multi-electrode arrays lack single-cell precision, whereas optical physiology generally requires advanced instrumentation that may not be universally available. Here we developed a simple, stimulation-free protocol with associated Matlab algorithms that enables scalable analyses of spontaneous network activity in cultured human and mouse neurons. The approach allows analysis of the overall network activity and of single-neuron dynamics, and is amenable to screening purposes. We validated the new protocol by assessing human neurons with a heterozygous conditional deletion of Munc18-1, and mouse neurons with a homozygous conditional deletion of neurexins. The approach described enabled identification of differential changes in these mutant neurons, allowing quantifications of the synchronous firing rate at the network level and of the amplitude and frequency of Ca2+-spikes at the single-neuron level. These results demonstrate the utility of the approach. Compared with current imaging platforms, our method is simple, scalable, accessible, and easy to implement. It enables quantification of more detailed parameters than multi-electrode arrays, but does not have the resolution and depth of more sophisticated yet labour-intensive methods, such as patch-clamp electrophysiology. The method reported here is scalable for a rapid direct assessment of neuronal function in culture, and can be applied to both human and mouse neurons. Thus, the method can serve as a basis for phenotypical analysis of mutations and for drug discovery efforts.	Action Potentials;Algorithms;Animals;Cells, Cultured;Mice;Neural Networks, Computer;Neurons;Optogenetics	Action Potentials;Algorithms;Animals;Cells;Cells, Cultured;Culture;Drug Discovery;Electrodes;Electrophysiology;Humans;Measures;Methods;Mice;Mutation;Neural Networks, Computer;Neurons;News;Optogenetics;Overall;Physiology;Screening;Synaptic Transmission	Automated image analysis;Ca(2+)-imaging;Human neurons;Munc18-1;Network activity;Neurexins;Synaptic connectivity;Synaptic transmission	Sun, Zijun;Südhof, Thomas C	[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine]		2	Journal of neuroscience methods	349		109041
U19MH104172	Group 1									10.1016/j.isci.2021.103115	34522848	2021	An interactive single cell web portal identifies gene and cell networks in COVID-19 host responses.	Numerous studies have provided single-cell transcriptome profiles of host responses to SARS-CoV-2 infection. Critically lacking however is a data mine that allows users to compare and explore cell profiles to gain insights and develop new hypotheses. To accomplish this, we harmonized datasets from COVID-19 and other control condition blood, bronchoalveolar lavage, and tissue samples, and derived a compendium of gene signature modules per cell type, subtype, clinical condition, and compartment. We demonstrate approaches to interacting with, exploring, and functional evaluating these modules via a new interactive web portal ToppCell (http://toppcell.cchmc.org/). As examples, we develop three hypotheses: (1) alternatively-differentiated monocyte-derived macrophages form a multicelllar signaling cascade that drives T cell recruitment and activation; (2) COVID-19-generated platelet subtypes exhibit dramatically altered potential to adhere, coagulate, and thrombose; and (3) extrafollicular B maturation is driven by a multilineage cell activation network that expresses an ensemble of genes strongly associated with risk for developing post-viral autoimmunity.		Autoimmunity;Blood;Blood Platelets;Bronchoalveolar Lavage;COVID-19;Cells;Dataset;Drive;Exhibition;Form;Gene Expression Profiles;Genes;Macrophages;News;Risk;T-Lymphocytes;Thrombosis;Tissues;Virology	AI/ML Bionetworks;Omics;Systems Immunobiology;Transcriptomics;Virology	Jin, Kang;Bardes, Eric E;Mitelpunkt, Alexis;Wang, Jake Y;Bhatnagar, Surbhi;Sengupta, Soma;Krummel, Daniel Pomeranz;Rothenberg, Marc E;Aronow, Bruce J	[Cincinnati Children's Hospital Medical Center, University of Cincinnati];[Cincinnati Children's Hospital Medical Center];[Cincinnati Children's Hospital Medical Center, Tel Aviv Sourasky Medical Center, Tel Aviv University];[Cincinnati Children's Hospital Medical Center];[Cincinnati Children's Hospital Medical Center, University of Cincinnati];[University of Cincinnati College of Medicine];[University of Cincinnati College of Medicine];[Cincinnati Children's Hospital Medical Center, University of Cincinnati];[Cincinnati Children's Hospital Medical Center, University of Cincinnati]		1	iScience	24	10	103115
U19MH104172	Group 1									10.1038/s41556-021-00650-9	33608689	2021	Author Correction: Optogenetic manipulation of cellular communication using engineered myosin motors.			Communication;Myosins;Optogenetics		Zhang, Zijian;Denans, Nicolas;Liu, Yingfei;Zhulyn, Olena;Rosenblatt, Hannah D;Wernig, Marius;Barna, Maria	[Stanford University];[Stanford University, Stowers Institute for Medical Research];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Xi'an Jiaotong University];[Stanford University];[Stanford University];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University];[Stanford University]		0	Nature cell biology	23	3	293
U19MH104172	Group 1					GSE168762				10.1073/pnas.2025598118	34035170	2021	Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons.	Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and additionally predispose to multiple other neurodevelopmental disorders. Engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multicenter effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. Using neurons transdifferentiated from induced pluripotent stem cells that were derived from schizophrenia patients carrying heterozygous NRXN1 deletions, we observed the same synaptic impairment as in engineered NRXN1-deficient neurons. This impairment manifested as a large decrease in spontaneous synaptic events, in evoked synaptic responses, and in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. Human NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene-expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.	Calcium-Binding Proteins;Case-Control Studies;Cell Transdifferentiation;Cells, Cultured;Cohort Studies;Embryonic Stem Cells;Gene Expression;Guanylate Kinases;Heterozygote;Humans;Induced Pluripotent Stem Cells;Mutation;Neural Cell Adhesion Molecules;Neurons;Neurotransmitter Agents;Schizophrenia	Calcium-Binding Proteins;Carrying;Case-Control Studies;Cell Transdifferentiation;Cells, Cultured;Cohort Studies;Depression;Drug Discovery;Embryonic Stem Cells;Exhibition;Future;Gene Expression;Genes;Genetic Background;Guanylate Kinases;Heterozygote;Humans;Induced Pluripotent Stem Cells;Laboratories;Methods;Mice;Mutation;Neural Cell Adhesion Molecules;Neurodevelopmental Disorders;Neurons;Neurotransmitter Agents;Neurotransmitters;Observation;Patients;Phenotype;Protein Binding;Pulse;Receptors, N-Methyl-D-Aspartate;Schizophrenia;Synapses;Synaptic Transmission	NMDA receptor;neurexin;schizophrenia;synapse formation;synaptic transmission	Pak, ChangHui;Danko, Tamas;Mirabella, Vincent R;Wang, Jinzhao;Liu, Yingfei;Vangipuram, Madhuri;Grieder, Sarah;Zhang, Xianglong;Ward, Thomas;Huang, Yu-Wen Alvin;Jin, Kang;Dexheimer, Philip;Bardes, Eric;Mitelpunkt, Alexis;Ma, Junyi;McLachlan, Michael;Moore, Jennifer C;Qu, Pingping;Purmann, Carolin;Dage, Jeffrey L;Swanson, Bradley J;Urban, Alexander E;Aronow, Bruce J;Pang, Zhiping P;Levinson, Douglas F;Wernig, Marius;Südhof, Thomas C	[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine, University of Massachusetts, Amherst];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Robert Wood Johnson Medical School];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, University School];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, University School];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, University School];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine];[Cincinnati Children's Hospital Medical Center, University of Cincinnati];[Cincinnati Children's Hospital Medical Center, University of Cincinnati];[Cincinnati Children's Hospital Medical Center, University of Cincinnati];[Cincinnati Children's Hospital Medical Center, Tel Aviv University, University of Cincinnati];[Fujifilm];[Fujifilm];[National Institute of Mental Health, Rutgers University];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Eli Lilly and Company];[Fujifilm];[Stanford University, Stanford University School of Medicine];[Cincinnati Children's Hospital Medical Center, University of Cincinnati];[Robert Wood Johnson Medical School];[Stanford University, Stanford University School of Medicine];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford University School of Medicine, University School];[Howard Hughes Medical Institute, Stanford University, Stanford University School of Medicine, University of Massachusetts, Amherst]	2.26	8	Proceedings of the National Academy of Sciences of the United States of America	118	22
U19MH104172	Group 1									10.1038/s41556-020-00625-2	33526902	2021	Optogenetic manipulation of cellular communication using engineered myosin motors.	Cells achieve highly efficient and accurate communication through cellular projections such as neurites and filopodia, yet there is a lack of genetically encoded tools that can selectively manipulate their composition and dynamics. Here, we present a versatile optogenetic toolbox of artificial multi-headed myosin motors that can move bidirectionally within long cellular extensions and allow for the selective transport of GFP-tagged cargo with light. Utilizing these engineered motors, we could transport bulky transmembrane receptors and organelles as well as actin remodellers to control the dynamics of both filopodia and neurites. Using an optimized in vivo imaging scheme, we further demonstrate that, upon limb amputation in axolotls, a complex array of filopodial extensions is formed. We selectively modulated these filopodial extensions and showed that they re-establish a Sonic Hedgehog signalling gradient during regeneration. Considering the ubiquitous existence of actin-based extensions, this toolbox shows the potential to manipulate cellular communication with unprecedented accuracy.	Actin Cytoskeleton;Ambystoma mexicanum;Animals;Biological Transport;Cell Communication;Cell Line;Cell Survival;Extremities;Green Fluorescent Proteins;Hedgehog Proteins;Kinetics;Light;Mice;Mouse Embryonic Stem Cells;Myosins;Neurites;Optogenetics;Protein Engineering;Pseudopodia;Regeneration;Signal Transduction;Transport Vesicles	Actin Cytoskeleton;Actins;Ambystoma mexicanum;Amputation;Animals;Biological Transport;Cell Communication;Cell Line;Cell Survival;Cells;Communication;Extremities;Filopodia;Green Fluorescent Proteins;Hedgehog Proteins;Hedgehogs;Kinetics;Light;Mice;Mouse Embryonic Stem Cells;Myosins;Neurites;Optogenetics;Organelles;Projection;Protein Engineering;Pseudopodia;Regeneration;Signal Transduction;Transport Vesicles		Zhang, Zijian;Denans, Nicolas;Liu, Yingfei;Zhulyn, Olena;Rosenblatt, Hannah D;Wernig, Marius;Barna, Maria	[Stanford University];[Stanford University, Stowers Institute for Medical Research];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Xi'an Jiaotong University];[Stanford University];[Stanford University];[Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University];[Stanford University]	3.23	11	Nature cell biology	23	2	198-208
U19MH107367	Group 2									10.1016/j.stemcr.2015.10.011	26610635	2015	Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders.	As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field.	Brain;Brain Diseases;Drug Discovery;Humans;Induced Pluripotent Stem Cells;Mosaicism;Neurogenesis;Precision Medicine	Brain;Brain Diseases;Cells;Disease;Drug Discovery;Future;Human Induced Pluripotent Stem Cells;Humans;In Vitro;Induced Pluripotent Stem Cells;Laboratories;Mosaicism;Neurogenesis;Opinions;Optimism;Outline;Patients;Precision Medicine		Brennand, Kristen J;Marchetto, M Carol;Benvenisty, Nissim;Brüstle, Oliver;Ebert, Allison;Izpisua Belmonte, Juan Carlos;Kaykas, Ajamete;Lancaster, Madeline A;Livesey, Frederick J;McConnell, Michael J;McKay, Ronald D;Morrow, Eric M;Muotri, Alysson R;Panchision, David M;Rubin, Lee L;Sawa, Akira;Soldner, Frank;Song, Hongjun;Studer, Lorenz;Temple, Sally;Vaccarino, Flora M;Wu, Jun;Vanderhaeghen, Pierre;Gage, Fred H;Jaenisch, Rudolf	[Icahn School of Medicine];[Salk Institute for Biological Studies];[Hebrew University of Jerusalem];[University of Bonn];[Medical College of Wisconsin];[Salk Institute for Biological Studies];[Novartis Institute for BioMedical Research];[MRC Laboratory of Molecular Biology];[The Gurdon Institute, University of Cambridge];[University of Virginia School of Medicine];[Lieber Institute for Brain Development];[Brown University];[University of California, San Diego];[National Institute of Mental Health];[Harvard University];[Johns Hopkins Hospital];[Whitehead Institute];[Johns Hopkins School of Medicine];[Memorial Sloan-Kettering Cancer Center];[Neural Stem Cell Institute];[Yale University];[Salk Institute for Biological Studies];[Université Libre de Bruxelles];[Salk Institute for Biological Studies];[Whitehead Institute]	2.07	57	Stem cell reports	5	6	933-945
U19MH107367	Group 2									10.1093/hmg/ddw008	26755826	2016	Cockayne syndrome-derived neurons display reduced synapse density and altered neural network synchrony.	Cockayne syndrome (CS) is a rare genetic disorder in which 80% of cases are caused by mutations in the Excision Repair Cross-Complementation group 6 gene (ERCC6). The encoded ERCC6 protein is more commonly referred to as Cockayne Syndrome B protein (CSB). Classical symptoms of CS patients include failure to thrive and a severe neuropathology characterized by microcephaly, hypomyelination, calcification and neuronal loss. Modeling the neurological aspect of this disease has proven difficult since murine models fail to mirror classical neurological symptoms. Therefore, a robust human in vitro cellular model would advance our fundamental understanding of the disease and reveal potential therapeutic targets. Herein, we successfully derived functional CS neural networks from human CS induced pluripotent stem cells (iPSCs) providing a new tool to facilitate studying this devastating disease. We identified dysregulation of the Growth Hormone/Insulin-like Growth Factor-1 (GH/IGF-1) pathway as well as pathways related to synapse formation, maintenance and neuronal differentiation in CSB neurons using unbiased RNA-seq gene expression analyses. Moreover, when compared to unaffected controls, CSB-deficient neural networks displayed altered electrophysiological activity, including decreased synchrony, and reduced synapse density. Collectively, our work reveals that CSB is required for normal neuronal function and we have established an alternative to previously available models to further study neural-specific aspects of CS.	Adolescent;Adult;Cell Differentiation;Cell Line;Child;Child, Preschool;Cockayne Syndrome;DNA Helicases;DNA Repair;DNA Repair Enzymes;Electrophysiological Phenomena;Female;Growth Hormone;Humans;Induced Pluripotent Stem Cells;Insulin-Like Growth Factor I;Male;Mutation;Nerve Net;Neurons;Poly-ADP-Ribose Binding Proteins;Signal Transduction;Synapses	Adolescent;Adult;Cell Differentiation;Cell Line;Child;Child, Preschool;Cockayne Syndrome;Comprehension;DNA Helicases;DNA Repair;DNA Repair Enzymes;Disease;Electrophysiological Phenomena;Excision Repair;Failure to Thrive;Female;Gene Expression;Genes;Growth Hormone;Hereditary Diseases;Humans;In Vitro;Induced Pluripotent Stem Cells;Insulin-Like Growth Factor I;Maintenance;Male;Microcephaly;Mutation;Nerve Net;Neurons;Neuropathology;News;Patients;Poly-ADP-Ribose Binding Proteins;Proteins;RNA-Seq;Signal Transduction;Somatomedins;Synapses;Therapeutics;Work		Vessoni, Alexandre T;Herai, Roberto H;Karpiak, Jerome V;Leal, Angelica M S;Trujillo, Cleber A;Quinet, Annabel;Agnez Lima, Lucymara F;Menck, Carlos F M;Muotri, Alysson R	[Institute of Biomedical Sciences, Academia Sinica, Rady Children's Hospital, University of California, San Diego, University of São Paulo];[Pontifical Catholic University of Paraná, Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Federal University of Rio Grande do Norte, Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Institute of Biomedical Sciences, Academia Sinica, University of São Paulo];[Federal University of Rio Grande do Norte];[Institute of Biomedical Sciences, Academia Sinica, University of São Paulo];[Rady Children's Hospital, University of California, San Diego]	0.87	20	Human molecular genetics	25	7	1271-80
U19MH107367	Group 2									10.1073/pnas.1524013113	26733678	2016	KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome.	Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K(+)-Cl(-) cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome.	Animals;Cells, Cultured;Humans;Induced Pluripotent Stem Cells;Male;Methyl-CpG-Binding Protein 2;Mice;Models, Biological;Mutation;Neurons;Repressor Proteins;Rett Syndrome;Symporters;gamma-Aminobutyric Acid	Animals;Autism Spectrum Disorder;Behavior;Brain;Cells, Cultured;Disease;Exhibition;Form;Genes;Humans;Induced Pluripotent Stem Cells;Lead;Male;Methyl-CpG-Binding Protein 2;Mice;Models, Biological;Mutation;Neurons;Patients;Regulation;Repressor Proteins;Rest;Rett Syndrome;Role;Symporters;Therapeutics;X Chromosome;gamma-Aminobutyric Acid	KCC2;MeCP2;Rett syndrome;disease modeling;human iPSC	Tang, Xin;Kim, Julie;Zhou, Li;Wengert, Eric;Zhang, Lei;Wu, Zheng;Carromeu, Cassiano;Muotri, Alysson R;Marchetto, Maria C N;Gage, Fred H;Chen, Gong	[Pennsylvania State University];[Pennsylvania State University];[Pennsylvania State University];[Bucknell University];[Pennsylvania State University];[Pennsylvania State University];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Salk Institute for Biological Studies];[Pennsylvania State University, Salk Institute for Biological Studies];[Pennsylvania State University, Salk Institute for Biological Studies]	5.19	114	Proceedings of the National Academy of Sciences of the United States of America	113	3	751-6
U19MH107367	Group 2									10.1038/nature18296	27279226	2016	The Brazilian Zika virus strain causes birth defects in experimental models.	Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKV(BR)) strain causes birth defects remains absent. Here we demonstrate that ZIKV(BR) infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKV(BR) crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKV(BR) outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKV(BR) in human neurodevelopment.	Animals;Apoptosis;Autophagy;Brain;Brazil;Cell Proliferation;Disease Models, Animal;Female;Fetal Growth Retardation;Fetus;Mice;Microcephaly;Neural Stem Cells;Organoids;Placenta;Pregnancy;Zika Virus;Zika Virus Infection	Aedes;Animals;Apoptosis;Arboviruses;Arthralgia;Asians;Autophagy;Blood;Brain;Brazil;Cell Death;Cell Proliferation;Central America;Congenital Abnormalities;Conjunctivitis;Culicidae;Disease;Disease Models, Animal;Disease Outbreaks;Efficiency;Epidemics;Exanthema;Experimental Model;Family;Female;Fetal Growth Retardation;Fetus;Fever;Flaviviridae;Flavivirus;French Polynesia;Guillain-Barre Syndrome;Humans;Infections;Islands;Macaca mulatta;Mice;Microcephaly;Micronesia;Neural Stem Cells;New Caledonia;Organoids;Patients;Placenta;Pregnancy;Report;Stem Cells;Therapeutics;Uganda;Viruses;Zika Virus;Zika Virus Infection		Cugola, Fernanda R;Fernandes, Isabella R;Russo, Fabiele B;Freitas, Beatriz C;Dias, João L M;Guimarães, Katia P;Benazzato, Cecília;Almeida, Nathalia;Pignatari, Graciela C;Romero, Sarah;Polonio, Carolina M;Cunha, Isabela;Freitas, Carla L;Brandão, Wesley N;Rossato, Cristiano;Andrade, David G;Faria, Daniele de P;Garcez, Alexandre T;Buchpigel, Carlos A;Braconi, Carla T;Mendes, Erica;Sall, Amadou A;Zanotto, Paolo M de A;Peron, Jean Pierre S;Muotri, Alysson R;Beltrão-Braga, Patricia C B	[University of São Paulo];[Rady Children's Hospital, University of California, San Diego, University of São Paulo];[University of São Paulo];[Rady Children's Hospital, University of California, San Diego];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[Rady Children's Hospital, University of California, San Diego];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[Pasteur Institute];[University of São Paulo];[University of São Paulo];[Rady Children's Hospital, University of California, San Diego];[University of São Paulo]	39.43	803	Nature	534	7606	267-71
U19MH107367	Group 2	Genomics				GSE67528				10.1038/mp.2016.95	27378147	2017	Altered proliferation and networks in neural cells derived from idiopathic autistic individuals.	Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.	Adolescent;Autism Spectrum Disorder;Autistic Disorder;Brain;Cell Proliferation;Cells, Cultured;Child;Child, Preschool;Female;Fibroblasts;Humans;Induced Pluripotent Stem Cells;Insulin-Like Growth Factor I;Male;Neural Stem Cells;Neurogenesis;Neurons;Tissue Culture Techniques;beta Catenin	Adolescent;Autism Spectrum Disorder;Autistic Disorder;Brain;Cell Proliferation;Cells;Cells, Cultured;Child;Child, Preschool;Clinical Trial;Endophenotypes;Female;Fibroblasts;Genetics;Growth Factors;Humans;Induced Pluripotent Stem Cells;Insulin;Insulin-Like Growth Factor I;Male;Neural Stem Cells;Neurodevelopmental Disorders;Neurogenesis;Neurons;Pathology;Pharmaceutical Preparations;Stem Cells;Therapeutic Effects;Tissue Culture Techniques;Work;beta Catenin		Marchetto, Maria C;Belinson, Haim;Tian, Yuan;Freitas, Beatriz C;Fu, Chen;Vadodaria, Krishna;Beltrao-Braga, Patricia;Trujillo, Cleber A;Mendes, Ana P D;Padmanabhan, Krishnan;Nunez, Yanelli;Ou, Jing;Ghosh, Himanish;Wright, Rebecca;Brennand, Kristen;Pierce, Karen;Eichenfield, Lawrence;Pramparo, Tiziano;Eyler, Lisa;Barnes, Cynthia C;Courchesne, Eric;Geschwind, Daniel H;Gage, Fred H;Wynshaw-Boris, Anthony;Muotri, Alysson R	[Salk Institute for Biological Studies];[University of California, San Francisco];[David Geffen School of Medicine, University of California, Los Angeles];[Rady Children's Hospital, University of California, San Diego];[Case Western Reserve University];[Salk Institute for Biological Studies];[Rady Children's Hospital, University of California, San Diego, University of São Paulo];[Rady Children's Hospital, University of California, San Diego];[Salk Institute for Biological Studies];[University of Rochester];[Rady Children's Hospital, Salk Institute for Biological Studies, University of California, San Diego];[David Geffen School of Medicine, University of California, Los Angeles];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Icahn School of Medicine];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[David Geffen School of Medicine, University of California, Los Angeles];[Salk Institute for Biological Studies];[Case Western Reserve University, University of California, San Francisco];[Rady Children's Hospital, University of California, San Diego]	9.11	194	Molecular psychiatry	22	6	820-835
U19MH107367	Group 2					GSE89036,GSE89405				10.1038/ni.3688	28218746	2017	Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing.	During microbial infection, responding CD8+ T lymphocytes differentiate into heterogeneous subsets that together provide immediate and durable protection. To elucidate the dynamic transcriptional changes that underlie this process, we applied a single-cell RNA-sequencing approach and analyzed individual CD8+ T lymphocytes sequentially throughout the course of a viral infection in vivo. Our analyses revealed a striking transcriptional divergence among cells that had undergone their first division and identified previously unknown molecular determinants that controlled the fate specification of CD8+ T lymphocytes. Our findings suggest a model for the differentiation of terminal effector cells initiated by an early burst of transcriptional activity and subsequently refined by epigenetic silencing of transcripts associated with memory lymphocytes, which highlights the power and necessity of single-cell approaches.	Animals;CD8-Positive T-Lymphocytes;Cell Differentiation;Cluster Analysis;Computational Biology;Epigenesis, Genetic;Gene Expression Profiling;Gene Silencing;Genetic Heterogeneity;Histones;Immunologic Memory;Lymphocyte Activation;Mice;Sequence Analysis, RNA;Single-Cell Analysis;T-Lymphocyte Subsets;Transcription, Genetic;Transcriptome	Animals;CD8-Positive T-Lymphocytes;Cell Differentiation;Cells;Cluster Analysis;Computational Biology;Epigenesis, Genetic;Epigenetics;Gene Expression Profiling;Gene Silencing;Genetic Heterogeneity;Histones;Immunologic Memory;Infections;Lymphocyte Activation;Lymphocytes;Memory;Mice;Power, Psychological;Regulation;Sequence Analysis, RNA;Sequence Determinations, RNA;Single-Cell Analysis;T-Lymphocyte Subsets;T-Lymphocytes;Transcription, Genetic;Transcriptome;Virus Diseases		Kakaradov, Boyko;Arsenio, Janilyn;Widjaja, Christella E;He, Zhaoren;Aigner, Stefan;Metz, Patrick J;Yu, Bingfei;Wehrens, Ellen J;Lopez, Justine;Kim, Stephanie H;Zuniga, Elina I;Goldrath, Ananda W;Chang, John T;Yeo, Gene W	[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[National University of Singapore, University of California, San Diego, Yong Loo Lin School of Medicine]	3.49	104	Nature immunology	18	4	422-432
U19MH107367	Group 2	Genomics				GSE47626				10.1093/hmg/ddx142	28430982	2017	Evidence of nuclei-encoded spliceosome mediating splicing of mitochondrial RNA.	Mitochondria are thought to have originated as free-living prokaryotes. Mitochondria organelles have small circular genomes with substantial structural and genetic similarity to bacteria. Contrary to the prevailing concept of intronless mitochondria, here we present evidence that mitochondrial RNA transcripts (mtRNA) are not limited to policystronic molecules, but also processed as nuclei-like transcripts that are differentially spliced and expressed in a cell-type specific manner. The presence of canonical splice sites in the mtRNA introns and of core components of the nuclei-encoded spliceosome machinery within the mitochondrial organelle suggest that nuclei-encoded spliceosome can mediate splicing of mtRNA.	Cell Nucleus;Genome;Humans;Introns;Mitochondria;RNA;RNA Splicing;RNA, Mitochondrial;Spliceosomes	Bacteria;Cell Nucleus;Cells;Genetics;Genome;Humans;Introns;Mediating;Mitochondria;Organelles;RNA;RNA Splicing;RNA, Mitochondrial;Spliceosomes;Thought		Herai, Roberto H;Negraes, Priscilla D;Muotri, Alysson R	[Pontifical Catholic University of Paraná, Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego]	0.37	8	Human molecular genetics	26	13	2472-2479
U19MH107367	Group 2									10.1093/hmg/ddw384	28007906	2017	IGF1 neuronal response in the absence of MECP2 is dependent on TRalpha 3.	Rett syndrome (RTT) is an X-linked neurodevelopmental disorder in which the MECP2 (methyl CpG-binding protein 2) gene is mutated. Recent studies showed that RTT-derived neurons have many cellular deficits when compared to control, such as: less synapses, lower dendritic arborization and reduced spine density. Interestingly, treatment of RTT-derived neurons with Insulin-like Growth Factor 1 (IGF1) could rescue some of these cellular phenotypes. Given the critical role of IGF1 during neurodevelopment, the present study used human induced pluripotent stem cells (iPSCs) from RTT and control individuals to investigate the gene expression profile of IGF1 and IGF1R on different developmental stages of differentiation. We found that the thyroid hormone receptor (TRalpha 3) has a differential expression profile. Thyroid hormone is critical for normal brain development. Our results showed that there is a possible link between IGF1/IGF1R and the TRalpha 3 and that over expression of IGF1R in RTT cells may be the cause of neurites improvement in neural RTT-derived neurons.	Cell Differentiation;Embryoid Bodies;Humans;Induced Pluripotent Stem Cells;Insulin-Like Growth Factor I;Methyl-CpG-Binding Protein 2;Neurodevelopmental Disorders;Neuronal Plasticity;Neurons;Receptor, IGF Type 1;Receptors, Somatomedin;Rett Syndrome;Spine;Synapses;Thyroid Hormone Receptors alpha;Transcriptome	Brain;Cell Differentiation;Cells;Dendritic Arborization;Embryoid Bodies;Gene Expression Profiles;Genes;Human Induced Pluripotent Stem Cells;Humans;Induced Pluripotent Stem Cells;Insulin-Like Growth Factor I;Methyl-CpG-Binding Protein 2;Neurites;Neurodevelopmental Disorders;Neuronal Plasticity;Neurons;Phenotype;Receptor, IGF Type 1;Receptors, Somatomedin;Receptors, Thyroid Hormone;Rett Syndrome;Role;Somatomedins;Spine;Synapses;Therapeutics;Thyroid Hormone Receptors alpha;Thyroid Hormones;Transcriptome		de Souza, Janaina S;Carromeu, Cassiano;Torres, Laila B;Araujo, Bruno H S;Cugola, Fernanda R;Maciel, Rui M B;Muotri, Alysson R;Giannocco, Gisele	[Federal University of São Paulo, Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Federal University of São Paulo];[Rady Children's Hospital, University of California, San Diego];[Federal University of São Paulo];[Rady Children's Hospital, University of California, San Diego];[Federal University of São Paulo]	0.94	17	Human molecular genetics	26	2	270-281
U19MH107367	Group 2									10.1016/j.brainres.2016.01.057	26854137	2017	Modeling autism spectrum disorders with human neurons.	Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impaired social communication and interactions and by restricted and repetitive behaviors. Although ASD is suspected to have a heritable or sporadic genetic basis, its underlying etiology and pathogenesis are not well understood. Therefore, viable human neurons and glial cells produced using induced pluripotent stem cells (iPSC) to reprogram cells from individuals affected with ASD provide an unprecedented opportunity to elucidate the pathophysiology of these disorders, providing novel insights regarding ASD and a potential platform to develop and test therapeutic compounds. Herein, we discuss the state of art with regards to ASD modeling, including limitations of this technology, as well as potential future directions. This article is part of a Special Issue entitled SI: Exploiting human neurons.	Animals;Autism Spectrum Disorder;Humans;Neurons	Animals;Art;Autism Spectrum Disorder;Behavior;Cells;Disease;Future;Genetics;Human Induced Pluripotent Stem Cells;Humans;Induced Pluripotent Stem Cells;Neurodevelopmental Disorders;Neuroglia;Neurons;Social Communication;Technology;Therapeutics	Autism spectrum disorders;Disease modeling;Human induced pluripotent stem cells;Human neurons	Beltrão-Braga, Patricia C B;Muotri, Alysson R	[Rady Children's Hospital, University of California, San Diego, University of São Paulo];[Rady Children's Hospital, University of California, San Diego]	0.60	14	Brain research	1656		49-54
U19MH107367	Group 2									10.1038/s41598-017-15467-6	29150641	2017	Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis.	One of the major challenges of the current Zika virus (ZIKV) epidemic is to prevent congenital foetal abnormalities, including microcephaly, following ZIKV infection of pregnant women. Given the urgent need for ZIKV prophylaxis and treatment, repurposing of approved drugs appears to be a viable and immediate solution. We demonstrate that the common anti-malaria drug chloroquine (CQ) extends the lifespan of ZIKV-infected interferon signalling-deficient AG129 mice. However, the severity of ZIKV infection in these mice precludes the study of foetal (vertical) viral transmission. Here, we show that interferon signalling-competent SJL mice support chronic ZIKV infection. Infected dams and sires are both able to transmit ZIKV to the offspring, making this an ideal model for in vivo validation of compounds shown to suppress ZIKV in cell culture. Administration of CQ to ZIKV-infected pregnant SJL mice during mid-late gestation significantly attenuated vertical transmission, reducing the ZIKV load in the foetal brain more than 20-fold. Given the limited side effects of CQ, its lack of contraindications in pregnant women, and its worldwide availability and low cost, we suggest that CQ could be considered for the treatment and prophylaxis of ZIKV.	Animals;Antimalarials;Chloroquine;Disease Models, Animal;Drug Repositioning;Humans;Mice;Neural Stem Cells;Spheroids, Cellular;Zika Virus;Zika Virus Infection	Administration;Animals;Antimalarials;Brain;Cell Culture Techniques;Chloroquine;Contraindications;Cost;Disease Models, Animal;Drug Repositioning;Epidemics;Humans;Infections;Interferons;Life Span;Malaria;Mice;Mice, 129 Strain;Microcephaly;Needs;Neural Stem Cells;Pharmaceutical Preparations;Pregnancy;Pregnant Women;Solutions;Spheroids, Cellular;Therapeutics;Zika Virus;Zika Virus Infection		Shiryaev, Sergey A;Mesci, Pinar;Pinto, Antonella;Fernandes, Isabella;Sheets, Nicholas;Shresta, Sujan;Farhy, Chen;Huang, Chun-Teng;Strongin, Alex Y;Muotri, Alysson R;Terskikh, Alexey V	[Sanford Burnham Prebys Medical Discovery Institute];[Rady Children's Hospital, University of California, San Diego];[Sanford Burnham Prebys Medical Discovery Institute];[Rady Children's Hospital, University of California, San Diego];[La Jolla Institute for Immunology];[La Jolla Institute for Immunology];[Sanford Burnham Prebys Medical Discovery Institute];[Sanford Burnham Prebys Medical Discovery Institute];[Sanford Burnham Prebys Medical Discovery Institute];[Rady Children's Hospital, University of California, San Diego];[Sanford Burnham Prebys Medical Discovery Institute]	4.91	81	Scientific reports	7	1	15771
U19MH107367	Group 2	Genomics				GSE85908				10.1016/j.molcel.2017.06.003	28673540	2017	Single-Cell Alternative Splicing Analysis with Expedition Reveals Splicing Dynamics during Neuron Differentiation.	Alternative splicing (AS) generates isoform diversity for cellular identity and homeostasis in multicellular life. Although AS variation has been observed among single cells, little is known about the biological or evolutionary significance of such variation. We developed Expedition, a computational framework consisting of outrigger, a de novo splice graph transversal algorithm to detect AS; anchor, a Bayesian approach to assign modalities; and bonvoyage, a visualization tool using non-negative matrix factorization to display modality changes. Applying Expedition to single pluripotent stem cells undergoing neuronal differentiation, we discover that up to 20% of AS exons exhibit bimodality. Bimodal exons are flanked by more conserved intronic sequences harboring distinct cis-regulatory motifs, constitute much of cell-type-specific splicing, are highly dynamic during cellular transitions, preserve reading frame, and reveal intricacy of cell states invisible to conventional gene expression analysis. Systematic AS characterization in single cells redefines our understanding of AS complexity in cell biology.	Algorithms;Alternative Splicing;Bayes Theorem;Cell Line;Computer Simulation;Evolution, Molecular;Gene Expression Regulation, Developmental;Humans;Kinetics;Male;Models, Genetic;Nerve Tissue Proteins;Neural Stem Cells;Neurogenesis;Neurons;Phenotype;Pluripotent Stem Cells;RNA, Messenger;Single-Cell Analysis	Algorithms;Alternative Splicing;Bayes Theorem;Bayesian Analysis;Biopharmaceuticals;Cell Biology;Cell Line;Cells;Classification;Comprehension;Computer Simulation;Evolution, Molecular;Exhibition;Exons;Expeditions;Gene Expression;Gene Expression Regulation, Developmental;Homeostasis;Humans;Kinetics;Life;Male;Models, Genetic;Nerve Tissue Proteins;Neural Stem Cells;Neurogenesis;Neurons;Phenotype;Pluripotent Stem Cells;Protein Isoforms;RNA Processing, Post-Transcriptional;RNA, Messenger;Reading Frames;Single-Cell Analysis;Stem Cells	RNA processing;alternative splicing;bimodality;differentiation;modality;neuron;post-transcription;single cell;stem cells	Song, Yan;Botvinnik, Olga B;Lovci, Michael T;Kakaradov, Boyko;Liu, Patrick;Xu, Jia L;Yeo, Gene W	[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[A*STAR, National University of Singapore, University of California, San Diego, Yong Loo Lin School of Medicine]	3.11	81	Molecular cell	67	1	148-161.e5
U19MH107367	Group 2	Review								10.1007/s00441-017-2685-x	28918504	2018	Autism spectrum disorders and disease modeling using stem cells.	Autism spectrum disorders (ASD) represent a variety of disorders characterized as complex lifelong neurodevelopment disabilities, which may affect the ability of communication and socialization, including typical comportments like repetitive and stereotyped behavior. Other comorbidities are usually present, such as echolalia, hypotonia, intellectual disability and difficulties in processing figured speech. Furthermore, some ASD individuals may present certain abilities, such as eidetic memory, outstanding musical or painting talents and special mathematical skills, among others. Considering the variability of the clinical symptoms, one autistic individual can be severely affected in communication while others can speak perfectly, sometimes having a vocabulary above average in early childhood. The same variability can be seen in other clinical symptoms, thus the "spectrum" can vary from severe to mild. Induced pluripotent stem cell technology has been used to model several neurological diseases, including syndromic and non-syndromic autism. We discuss how modeling the central nervous system cells in a dish may help to reach a better understanding of ASD pathology and variability, as well as personalize their treatment.	Animals;Autism Spectrum Disorder;Culture Techniques;Humans;Induced Pluripotent Stem Cells;Mice;Models, Neurological;Neurons	Ability;Affect;Animals;Autism Spectrum Disorder;Autistic Disorder;Cells;Central Nervous System;Communication;Comorbidity;Comprehension;Culture Techniques;Disease;Echolalia;Humans;Induced Pluripotent Stem Cells;Intellectual Disability;Memory;Mice;Models, Neurological;Muscle Hypotonia;Neurons;Paintings;Pathology;Socialization;Speech;Stem Cells;Stereotyped Behavior;Talent;Technology;Therapeutics;Vocabulary	ASD;Autism spectrum disorders;Disease modeling;Stem cells;iPSC	Brito, Anita;Russo, Fabiele Baldino;Muotri, Alysson Renato;Beltrão-Braga, Patricia Cristina Baleeiro	[Institute of Biomedical Sciences, Academia Sinica, University of São Paulo];[Institute of Biomedical Sciences, Academia Sinica, University of São Paulo];[Rady Children's Hospital, University of California, San Diego];[Institute of Biomedical Sciences, Academia Sinica, University of São Paulo]	0.42	7	Cell and tissue research	371	1	153-160
U19MH107367	Group 2									10.1038/s41598-018-19526-4	29352135	2018	Blocking Zika virus vertical transmission.	The outbreak of the Zika virus (ZIKV) has been associated with increased incidence of congenital malformations. Although recent efforts have focused on vaccine development, treatments for infected individuals are needed urgently. Sofosbuvir (SOF), an FDA-approved nucleotide analog inhibitor of the Hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) was recently shown to be protective against ZIKV both in vitro and in vivo. Here, we show that SOF protected human neural progenitor cells (NPC) and 3D neurospheres from ZIKV infection-mediated cell death and importantly restored the antiviral immune response in NPCs. In vivo, SOF treatment post-infection (p.i.) decreased viral burden in an immunodeficient mouse model. Finally, we show for the first time that acute SOF treatment of pregnant dams p.i. was well-tolerated and prevented vertical transmission of the virus to the fetus. Taken together, our data confirmed SOF-mediated sparing of human neural cell types from ZIKV-mediated cell death in vitro and reduced viral burden in vivo in animal models of chronic infection and vertical transmission, strengthening the growing body of evidence for SOF anti-ZIKV activity.		Antiviral Agents;Cell Death;Cells;Disease Outbreaks;Fetus;Hepatitis C;Humans;Immunity;In Vitro;Incidence;Infections;Mice;Models, Animal;Nucleotides;RNA-Dependent RNA Polymerase;Sofosbuvir;Stem Cells;Therapeutics;Time;Vaccines;Viral Load;Viruses;Zika Virus		Mesci, Pinar;Macia, Angela;Moore, Spencer M;Shiryaev, Sergey A;Pinto, Antonella;Huang, Chun-Teng;Tejwani, Leon;Fernandes, Isabella R;Suarez, Nicole A;Kolar, Matthew J;Montefusco, Sandro;Rosenberg, Scott C;Herai, Roberto H;Cugola, Fernanda R;Russo, Fabiele B;Sheets, Nicholas;Saghatelian, Alan;Shresta, Sujan;Momper, Jeremiah D;Siqueira-Neto, Jair L;Corbett, Kevin D;Beltrão-Braga, Patricia C B;Terskikh, Alexey V;Muotri, Alysson R	[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Sanford Burnham Prebys Medical Discovery Institute];[Sanford Burnham Prebys Medical Discovery Institute];[Sanford Burnham Prebys Medical Discovery Institute];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Salk Institute for Biological Studies];[University of California, San Diego];[Ludwig Cancer Research, University of California, San Diego];[Pontifical Catholic University of Paraná];[University of São Paulo, University of São Paulo School of Medicine];[University of São Paulo, University of São Paulo School of Medicine];[La Jolla Institute for Immunology];[Salk Institute for Biological Studies];[La Jolla Institute for Immunology];[University of California, San Diego];[University of California, San Diego];[Ludwig Cancer Research];[University of São Paulo, University of São Paulo School of Medicine];[Sanford Burnham Prebys Medical Discovery Institute];[Rady Children's Hospital, University of California, San Diego]	2.14	32	Scientific reports	8	1	1218
U19MH107367	Group 2									10.1089/scd.2018.0112	30142987	2018	Direct Generation of Human Cortical Organoids from Primary Cells.	The study of variations in human neurodevelopment and cognition is limited by the availability of experimental models. While animal models only partially recapitulate the human brain development, genetics, and heterogeneity, human-induced pluripotent stem cells can provide an attractive experimental alternative. However, cellular reprogramming and further differentiation techniques are costly and time-consuming and therefore, studies using this approach are often limited to a small number of samples. In this study, we describe a rapid and cost-effective method to reprogram somatic cells and the direct generation of cortical organoids in a 96-well format. Our data are a proof-of-principle that a large cohort of samples can be generated for experimental assessment of the human neural development.	Animals;Brain;Cell Culture Techniques;Cell Differentiation;Cellular Reprogramming;Humans;Induced Pluripotent Stem Cells;Organoids	Animals;Brain;Cell Culture Techniques;Cell Differentiation;Cells;Cellular Reprogramming;Cognition;Cost;Experimental Model;Generations;Genetics;Human Induced Pluripotent Stem Cells;Humans;Induced Pluripotent Stem Cells;Methods;Models, Animal;Organoids;Time	high-throughput;induced pluripotent stem cell;neural development;organoids	Schukking, Monique;Miranda, Helen C;Trujillo, Cleber A;Negraes, Priscilla D;Muotri, Alysson R	[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego]	0.29	5	Stem cells and development	27	22	1549-1556
U19MH107367	Group 2	Review								10.1002/dneu.22584	29484850	2018	Genetic variations on SETD5 underlying autistic conditions.	The prevalence of autism spectrum disorders (ASD) and the number of identified ASD-related genes have increased in recent years. The SETD5 gene encodes a SET-containing-domain 5 protein, a likely reader enzyme. Genetic evidences suggest that SETD5 malfunction contributes to ASD phenotype, such as on intellectual disability (ID) and facial dysmorphism. In this review, we mapped the clinical phenotypes of individuals carrying mutations on the SETD5 gene that are associated with ASD and other chromatinopathies (mutation in epigenetic modifiers that leads to the development of neurodevelopmental disorders such as ASD). After a detailed systematic literature review and analysis of public disease-related databank, we found so far 42 individuals carrying mutations on the SETD5 gene, with 23.8% presenting autistic-like features. Furthermore, most of mutations occurred between positions 9,480,000-9,500,000 bp on chromosome 3 (3p25.3) at the SETD5 gene locus. In all males, mutations in SETD5 presented high penetrance, while in females the clinical phenotype seems more variable with two reported cases showing normal female carriers and not presenting ASD or any ID-like symptoms. At the molecular level, SETD5 interacts with proteins of PAF1C and N-CoR complexes, leading to a possible involvement with chromatin modification pathway, which plays important roles for brain development. Together, we propose that mutations on the SETD5 gene could lead to a new syndromic condition in males, which is linked to 3p25 syndrome, and can leads to ASD-related intellectual disability and facial dysmorphism. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 500-518, 2018.	Animals;Autism Spectrum Disorder;Genetic Variation;Humans;Methyltransferases	Animals;Autism Spectrum Disorder;Autistic Disorder;Brain;Carrying;Chromatin;Chromosomes, Human, Pair 3;Classification;Disease;Enzymes;Epigenetics;Female;Genes;Genetic Variation;Genetics;Humans;Id;Intellectual Disability;Lead;Literature;Male;Methyltransferases;Mutation;Neurodevelopmental Disorders;News;Penetrance;Periodical;Phenotype;Play;Prevalence;Proteins;Review;Role;Staphylococcal Protein A;Syndrome	SETD5 gene;SETD5 syndrome;autism spectrum disorder;genetic variants;intellectual disability;syndromic autism	Fernandes, Isabella R;Cruz, Ana C P;Ferrasa, Adriano;Phan, Dylan;Herai, Roberto H;Muotri, Alysson R	[Rady Children's Hospital, University of California, San Diego];[Pontifical Catholic University of Paraná];[Pontifical Catholic University of Paraná, State University of Ponta Grossa];[Rady Children's Hospital, University of California, San Diego];[Pontifical Catholic University of Paraná];[Rady Children's Hospital, University of California, San Diego]	0.91	17	Developmental neurobiology	78	5	500-518
U19MH107367	Group 2									10.1093/hmg/ddx382	29048558	2018	Modeling neuro-immune interactions during Zika virus infection.	Although Zika virus (ZIKV) infection is often asymptomatic, in some cases, it can lead to birth defects in newborns or serious neurologic complications in adults. However, little is known about the interplay between immune and neural cells that could contribute to the ZIKV pathology. To understand the mechanisms at play during infection and the antiviral immune response, we focused on neural precursor cells (NPCs)-microglia interactions. Our data indicate that human microglia infected with the current circulating Brazilian ZIKV induces a similar pro-inflammatory response found in ZIKV-infected human tissues. Importantly, using our model, we show that microglia interact with ZIKV-infected NPCs and further spread the virus. Finally, we show that Sofosbuvir, an FDA-approved drug for Hepatitis C, blocked viral infection in NPCs and therefore the transmission of the virus from microglia to NPCs. Thus, our model provides a new tool for studying neuro-immune interactions and a platform to test new therapeutic drugs.	Cell Line;Humans;Induced Pluripotent Stem Cells;Microglia;Models, Biological;Neural Stem Cells;Sofosbuvir;Zika Virus;Zika Virus Infection	Adult;Antiviral Agents;Cell Line;Cells;Congenital Abnormalities;Hepatitis C;Humans;Immunity;Induced Pluripotent Stem Cells;Infant, Newborn;Infections;Lead;Microglia;Models, Biological;Neural Stem Cells;Neuroimmunomodulation;News;Pathology;Pharmaceutical Preparations;Play;Sofosbuvir;Therapeutics;Tissues;Virus Diseases;Viruses;Zika Virus;Zika Virus Infection		Mesci, Pinar;Macia, Angela;LaRock, Christopher N;Tejwani, Leon;Fernandes, Isabella R;Suarez, Nicole A;de A Zanotto, Paolo M;Beltrão-Braga, Patricia C B;Nizet, Victor;Muotri, Alysson R	[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[University of São Paulo];[University of São Paulo];[University of California, San Diego];[Rady Children's Hospital, University of California, San Diego]	1.31	25	Human molecular genetics	27	1	41-52
U19MH107367	Group 2	Electrophysiology								10.1016/j.biopsych.2017.09.021	29129319	2018	Modeling the Interplay Between Neurons and Astrocytes in Autism Using Human Induced Pluripotent Stem Cells.	Autism spectrum disorder (ASD) is a neurodevelopmental disorder with unclear etiology and imprecise genetic causes. The main goal of this work was to investigate neuronal connectivity and the interplay between neurons and astrocytes from individuals with nonsyndromic ASD using induced pluripotent stem cells. Induced pluripotent stem cells were derived from a clinically well-characterized cohort of three individuals with nonsyndromic ASD sharing common behaviors and three control subjects, two clones each. We generated mixed neural cultures analyzing synaptogenesis and neuronal activity using a multielectrode array platform. Furthermore, using an enriched astrocyte population, we investigated their role in neuronal maintenance. ASD-derived neurons had a significant decrease in synaptic gene expression and protein levels, glutamate neurotransmitter release, and, consequently, reduced spontaneous firing rate. Based on co-culture experiments, we observed that ASD-derived astrocytes interfered with proper neuronal development. In contrast, control-derived astrocytes rescued the morphological neuronal phenotype and synaptogenesis defects from ASD neuronal co-cultures. Furthermore, after identifying interleukin-6 secretion from astrocytes in individuals with ASD as a possible culprit for neural defects, we were able to increase synaptogenesis by blocking interleukin-6 levels. Our findings reveal the contribution of astrocytes to neuronal phenotype and confirm previous studies linking interleukin-6 and autism, suggesting potential novel therapeutic pathways for a subtype of individuals with ASD. This is the first report demonstrating that glial dysfunctions could contribute to nonsyndromic autism pathophysiology using induced pluripotent stem cells modeling disease technology.	Astrocytes;Autism Spectrum Disorder;Cell Culture Techniques;Child;Female;Gene Expression;Humans;Induced Pluripotent Stem Cells;Interleukin-6;Male;Models, Neurological;Neurons;Synapses	Astrocytes;Autism Spectrum Disorder;Autistic Disorder;Behavior;Bodily Secretions;Cell Culture Techniques;Child;Clone Cells;Coculture Techniques;Culture;Disease;Female;Gene Expression;Genetics;Glutamates;Goals;Human Induced Pluripotent Stem Cells;Humans;Induced Pluripotent Stem Cells;Interleukin-6;Maintenance;Male;Models, Neurological;Neurodevelopmental Disorders;Neurons;Neurotransmitters;Phenotype;Population;Proteins;Report;Role;Synapses;Technology;Therapeutics;Work	ASD;Astrocytes;Autism;Co-culture model;Neurons;iPSCs	Russo, Fabiele Baldino;Freitas, Beatriz Camille;Pignatari, Graciela Conceição;Fernandes, Isabella Rodrigues;Sebat, Jonathan;Muotri, Alysson Renato;Beltrão-Braga, Patricia Cristina Baleeiro	[Institute of Biomedical Sciences, Academia Sinica, University of São Paulo];[Rady Children's Hospital, University of California, San Diego];[Institute of Biomedical Sciences, Academia Sinica, University of São Paulo];[Rady Children's Hospital, University of California, San Diego, University of São Paulo];[University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Institute of Biomedical Sciences, Academia Sinica, University of São Paulo]	4.44	70	Biological psychiatry	83	7	569-578
U19MH107367	Group 2	Review								10.3389/fnmol.2018.00261	30147644	2018	Patch-Seq Protocol to Analyze the Electrophysiology, Morphology and Transcriptome of Whole Single Neurons Derived From Human Pluripotent Stem Cells.	The human brain is composed of a complex assembly of about 171 billion heterogeneous cellular units (86 billion neurons and 85 billion non-neuronal glia cells). A comprehensive description of brain cells is necessary to understand the nervous system in health and disease. Recently, advances in genomics have permitted the accurate analysis of the full transcriptome of single cells (scRNA-seq). We have built upon such technical progress to combine scRNA-seq with patch-clamping electrophysiological recording and morphological analysis of single human neurons in vitro. This new powerful method, referred to as Patch-seq, enables a thorough, multimodal profiling of neurons and permits us to expose the links between functional properties, morphology, and gene expression. Here, we present a detailed Patch-seq protocol for isolating single neurons from in vitro neuronal cultures. We have validated the Patch-seq whole-transcriptome profiling method with human neurons generated from embryonic and induced pluripotent stem cells (ESCs/iPSCs) derived from healthy subjects, but the procedure may be applied to any kind of cell type in vitro. Patch-seq may be used on neurons in vitro to profile cell types and states in depth to unravel the human molecular basis of neuronal diversity and investigate the cellular mechanisms underlying brain disorders.		Brain;Brain Diseases;Cells;Clamping;Culture;Disease;Electrophysiology;Gene Expression;Gene Expression Profiling;Genomics;Health;Healthy Volunteers;Humans;In Vitro;Induced Pluripotent Stem Cells;Methods;Nervous System;Neuroglia;Neurons;News;Permits;Pluripotent Stem Cells;Procedures;RNA, Small Cytoplasmic;RNA-Seq;Transcriptome	cellular phenotyping;electrophysiology;human neuron transcriptome;induced pluripotent stem cell (iPSC);neuronal diversity;patch clamping;patch-seq;single-cell RNA-seq	van den Hurk, Mark;Erwin, Jennifer A;Yeo, Gene W;Gage, Fred H;Bardy, Cedric	[South Australian Health and Medical Research Institute];[Johns Hopkins University, Lieber Institute for Brain Development];[National University of Singapore, University of California, San Diego, Yong Loo Lin School of Medicine];[Salk Institute for Biological Studies];[Flinders University, South Australian Health and Medical Research Institute]	1.06	20	Frontiers in molecular neuroscience	11		261
U19MH107367	Group 2									10.1126/scitranslmed.aam6651	29743351	2018	Survival of syngeneic and allogeneic iPSC-derived neural precursors after spinal grafting in minipigs.	The use of autologous (or syngeneic) cells derived from induced pluripotent stem cells (iPSCs) holds great promise for future clinical use in a wide range of diseases and injuries. It is expected that cell replacement therapies using autologous cells would forego the need for immunosuppression, otherwise required in allogeneic transplantations. However, recent studies have shown the unexpected immune rejection of undifferentiated autologous mouse iPSCs after transplantation. Whether similar immunogenic properties are maintained in iPSC-derived lineage-committed cells (such as neural precursors) is relatively unknown. We demonstrate that syngeneic porcine iPSC-derived neural precursor cell (NPC) transplantation to the spinal cord in the absence of immunosuppression is associated with long-term survival and neuronal and glial differentiation. No tumor formation was noted. Similar cell engraftment and differentiation were shown in spinally injured transiently immunosuppressed swine leukocyte antigen (SLA)-mismatched allogeneic pigs. These data demonstrate that iPSC-NPCs can be grafted into syngeneic recipients in the absence of immunosuppression and that temporary immunosuppression is sufficient to induce long-term immune tolerance after NPC engraftment into spinally injured allogeneic recipients. Collectively, our results show that iPSC-NPCs represent an alternative source of transplantable NPCs for the treatment of a variety of disorders affecting the spinal cord, including trauma, ischemia, or amyotrophic lateral sclerosis.	Aging;Animals;Cell Differentiation;Cellular Reprogramming;Chronic Disease;Fibroblasts;Gene Expression Regulation;Immune Tolerance;Immunity, Humoral;Immunosuppression Therapy;Induced Pluripotent Stem Cells;Neostriatum;Neural Stem Cells;Neurons;Rats;Skin;Spinal Cord;Spinal Cord Injuries;Survival Analysis;Swine;Swine, Miniature;Transplantation, Homologous;Transplantation, Isogeneic	Aging;Amyotrophic Lateral Sclerosis;Animals;Cell Differentiation;Cells;Cellular Reprogramming;Chronic Disease;Disease;Fibroblasts;Future;Gene Expression Regulation;HLA Antigens;Immune Tolerance;Immunity, Humoral;Immunosuppression;Induced Pluripotent Stem Cells;Injuries;Ischemia;Mice;Needs;Neoplasms;Neostriatum;Neural Stem Cells;Neurons;Rats;Skin;Spinal Cord;Spinal Cord Injuries;Survival;Survival Analysis;Swine;Swine, Miniature;Therapeutics;Transplantation;Transplantation, Homologous;Transplantation, Isogeneic;Wounds and Injuries		Strnadel, Jan;Carromeu, Cassiano;Bardy, Cedric;Navarro, Michael;Platoshyn, Oleksandr;Glud, Andreas N;Marsala, Silvia;Kafka, Jozef;Miyanohara, Atsushi;Kato, Tomohisa;Tadokoro, Takahiro;Hefferan, Michael P;Kamizato, Kota;Yoshizumi, Tetsuya;Juhas, Stefan;Juhasova, Jana;Ho, Chak-Sum;Kheradmand, Taba;Chen, PeiXi;Bohaciakova, Dasa;Hruska-Plochan, Marian;Todd, Andrew J;Driscoll, Shawn P;Glenn, Thomas D;Pfaff, Samuel L;Klima, Jiri;Ciacci, Joseph;Curtis, Eric;Gage, Fred H;Bui, Jack;Yamada, Kazuhiko;Muotri, Alysson R;Marsala, Martin	[Comenius University, Jessenius Faculty of Medicine, University of California, San Diego];[University of California, San Diego];[Salk Institute for Biological Studies, South Australian Health and Medical Research Institute];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Center for iPS Cell Research and Application, Kyoto University];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Czech Academy of Sciences];[Czech Academy of Sciences];;;[University of California, San Diego];[Masaryk University, University of California, San Diego];[University of California, San Diego, University of Zurich];[University of Glasgow];[Howard Hughes Medical Institute, Salk Institute for Biological Studies];[Howard Hughes Medical Institute, Salk Institute for Biological Studies];[Howard Hughes Medical Institute, Salk Institute for Biological Studies];[Czech Academy of Sciences];[University of California, San Diego];[University of California, San Diego];[Salk Institute for Biological Studies];[University of California, San Diego];[Columbia University Medical Center];[University of California, San Diego];[Slovak Academy of Sciences, University of California, San Diego]	1.99	29	Science translational medicine	10	440
U19MH107367	Group 2									10.1016/j.mcp.2017.12.005	29305905	2018	The contribution of GTF2I haploinsufficiency to Williams syndrome.	Williams syndrome (WS) is a neurodevelopmental disorder involving hemideletion of as many as 26-28 genes, resulting in a constellation of unique physical, cognitive and behavior phenotypes. The haploinsufficiency effect of each gene has been studied and correlated with phenotype(s) using several models including WS subjects, animal models, and peripheral cell lines. However, links for most of the genes to WS phenotypes remains unclear. Among those genes, general transcription factor 2I (GTF2I) is of particular interest as its haploinsufficiency is possibly associated with hypersociability in WS. Here, we describe studies of atypical WS cases as well as mouse models focusing on GTF2I that support a role for this protein in the neurocognitive and behavioral profiles of WS individuals. We also review collective studies on diverse molecular functions of GTF2I that may provide mechanistic explanation for phenotypes recently reported in our relevant cellular model, namely WS induced pluripotent stem cell (iPSC)-derived neurons. Finally, in light of the progress in gene-manipulating approaches, we suggest their uses in revealing the neural functions of GTF2I in the context of WS.	Animals;Genetic Association Studies;Genetic Predisposition to Disease;Haploinsufficiency;Humans;Models, Biological;Transcription Factors, TFII;Williams Syndrome	Animals;Behavior;Cell Line;Genes;Genetic Association Studies;Genetic Predisposition to Disease;Haploinsufficiency;Humans;Induced Pluripotent Stem Cells;Light;Mice;Models, Animal;Models, Biological;Neurodevelopmental Disorders;Neurons;Phenotype;Proteins;Review;Role;Transcription Factors, General;Transcription Factors, TFII;Williams Syndrome	GTF2I;Hypersociability;TRPC3;Williams syndrome	Chailangkarn, Thanathom;Noree, Chalongrat;Muotri, Alysson R	;[Mahidol University];[Rady Children's Hospital, University of California, San Diego]	0.50	9	Molecular and cellular probes	40		45-51
U19MH107367	Group 2									10.1016/j.neuron.2019.03.014	30998900	2019	Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions.	RNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such as aberrant RNA splicing, transport, and stability. Disruption of RNA binding proteins and widespread RNA processing defects are increasingly recognized as critical determinants of neurological diseases. Here, we describe distinct mechanisms by which the homeostasis of RNA binding proteins is compromised in neurological disorders through their reduced expression level, increased propensity to aggregate or sequestration by abnormal RNAs. These mechanisms all converge toward altered neuronal function highlighting the susceptibility of neurons to deleterious changes in RNA expression and the central role of RNA binding proteins in preserving neuronal integrity. Emerging therapeutic approaches to mitigate or reverse alterations of RNA binding proteins in neurological diseases are discussed.	Animals;Autophagy;CRISPR-Cas Systems;Genetic Therapy;Genetic Vectors;Homeostasis;Humans;Molecular Targeted Therapy;Nervous System Diseases;Oligoribonucleotides, Antisense;Paraneoplastic Syndromes, Nervous System;RNA;RNA Processing, Post-Transcriptional;RNA Splicing;RNA Stability;RNA Transport;RNA-Binding Proteins	Animals;Autistic Disorder;Autophagy;CRISPR-Cas Systems;Dementia;Disease;Genetic Therapy;Genetic Vectors;Heterogeneous-Nuclear Ribonucleoproteins;Homeostasis;Humans;Life Cycle Stages;Maintenance;Metabolism;Molecular Targeted Therapy;Nervous System Diseases;Neurons;Oligoribonucleotides, Antisense;Paraneoplastic Syndromes, Nervous System;Phenotype;Proteins;RNA;RNA Processing, Post-Transcriptional;RNA Splicing;RNA Stability;RNA Transport;RNA-Binding Proteins;Regulation;Role;Therapeutics;Transcriptome	ALS;FMRP;RNA binding protein;Repeat expansion;SMA;SMN;TDP-43;autism;dementia;hnRNP	Nussbacher, Julia K;Tabet, Ricardos;Yeo, Gene W;Lagier-Tourenne, Clotilde	[University of California, San Diego];[Harvard Medical School, Harvard University, Massachusetts General Hospital];[University of California, San Diego];[Harvard Medical School, Harvard University, Kurume University, Massachusetts General Hospital]	6.31	84	Neuron	102	2	294-320
U19MH107367	Group 2	Imaging								10.1073/pnas.1902513116	31320591	2019	Exosomes regulate neurogenesis and circuit assembly.	Exosomes are thought to be released by all cells in the body and to be involved in intercellular communication. We tested whether neural exosomes can regulate the development of neural circuits. We show that exosome treatment increases proliferation in developing neural cultures and in vivo in dentate gyrus of P4 mouse brain. We compared the protein cargo and signaling bioactivity of exosomes released by hiPSC-derived neural cultures lacking MECP2, a model of the neurodevelopmental disorder Rett syndrome, with exosomes released by isogenic rescue control neural cultures. Quantitative proteomic analysis indicates that control exosomes contain multiple functional signaling networks known to be important for neuronal circuit development. Treating MECP2-knockdown human primary neural cultures with control exosomes rescues deficits in neuronal proliferation, differentiation, synaptogenesis, and synchronized firing, whereas exosomes from MECP2-deficient hiPSC neural cultures lack this capability. These data indicate that exosomes carry signaling information required to regulate neural circuit development.	Action Potentials;Animals;Cell Count;Cell Differentiation;Cell Proliferation;Cells, Cultured;Dentate Gyrus;Exosomes;Humans;Induced Pluripotent Stem Cells;Methyl-CpG-Binding Protein 2;Mice;Nerve Net;Neurogenesis;Neurons;Signal Transduction;Spheroids, Cellular;Synapses	Action Potentials;Animals;Brain;Cell Count;Cell Differentiation;Cell Proliferation;Cells;Cells, Cultured;Communication;Culture;Dentate Gyrus;Exosomes;Extracellular Vesicles;Human Induced Pluripotent Stem Cells;Humans;Induced Pluripotent Stem Cells;Methyl-CpG-Binding Protein 2;Mice;Nerve Net;Neurodevelopmental Disorders;Neurogenesis;Neurons;Proteins;Proteomics;Rett Syndrome;Signal Transduction;Spheroids, Cellular;Synapses;Therapeutics;Thought	Rett syndrome;exosomes;extracellular vesicle;neuronal development;synaptogenesis	Sharma, Pranav;Mesci, Pinar;Carromeu, Cassiano;McClatchy, Daniel R;Schiapparelli, Lucio;Yates, John R;Muotri, Alysson R;Cline, Hollis T	[Scripps Research];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Scripps Research];[Scripps Research];[Scripps Research];[Rady Children's Hospital, University of California, San Diego];[Scripps Research]	8.28	91	Proceedings of the National Academy of Sciences of the United States of America	116	32	16086-16094
U19MH107367	Group 2									10.1016/j.mito.2018.09.005	30218715	2019	Frequency and association of mitochondrial genetic variants with neurological disorders.	Mitochondria are small cytosolic organelles and the main source of energy production for the cells, especially in the brain. This organelle has its own genome, the mitochondrial DNA (mtDNA), and genetic variants in this molecule can alter the normal energy metabolism in the brain, contributing to the development of a wide assortment of Neurological Disorders (ND), including neurodevelopmental syndromes, neurodegenerative diseases and neuropsychiatric disorders. These ND are comprised by a heterogeneous group of syndromes and diseases that encompass different cognitive phenotypes and behavioral disorders, such as autism, Asperger's syndrome, pervasive developmental disorder, attention deficit hyperactivity disorder, Huntington disease, Leigh Syndrome and bipolar disorder. In this work we carried out a Systematic Literature Review (SLR) to identify and describe the mitochondrial genetic variants associated with the occurrence of ND. Most of genetic variants found in mtDNA were associated with Single Nucleotide Polimorphisms (SNPs), ~79%, with ~15% corresponding to deletions, ~3% to Copy Number Variations (CNVs), ~2% to insertions and another 1% included mtDNA replication problems and genetic rearrangements. We also found that most of the variants were associated with coding regions of mitochondrial proteins but were also found in regulatory transcripts (tRNA and rRNA) and in the D-Loop replication region of the mtDNA. After analysis of mtDNA deletions and CNV, none of them occur in the D-Loop region. This SLR shows that all transcribed mtDNA molecules have mutations correlated with ND. Finally, we describe that all mtDNA variants found were associated with deterioration of cognitive (dementia) and intellectual functions, learning disabilities, developmental delays, and personality and behavior problems.	DNA, Mitochondrial;Genetic Predisposition to Disease;Genetic Variation;Humans;Nervous System Diseases	Asperger Syndrome;Association;Attention Deficit Disorder with Hyperactivity;Autistic Disorder;Bipolar Disorder;Brain;Cells;Classification;Coding;DNA, Mitochondrial;Dementia;Disease;Energy Metabolism;Genetic Predisposition to Disease;Genetic Variation;Genetics;Genome;Humans;Huntington Disease;Learning Disabilities;Leigh Disease;Literature;Mitochondria;Mitochondrial Proteins;Mutation;Nervous System Diseases;Neurodegenerative Diseases;Nucleotides;Organelles;Personality;Phenotype;Polymorphism, Single Nucleotide;Problem Behavior;Production;RNA;RNA, Transfer;Review;Syndrome;Work	Genetic variants;Mitochondrial DNA;Neurodegenerative diseases;Neurodevelopmental syndromes;Neurological disorders;Neuropsychiatric disorders;Systematic literature review	Cruz, Ana Carolina P;Ferrasa, Adriano;Muotri, Alysson R;Herai, Roberto H	[Pontifical Catholic University of Paraná];[Pontifical Catholic University of Paraná, State University of Ponta Grossa];[Rady Children's Hospital, University of California, San Diego];[Pontifical Catholic University of Paraná]	1.07	10	Mitochondrion	46		345-360
U19MH107367	Group 2	Imaging								10.1016/j.celrep.2019.01.028	30699348	2019	Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease.	Spinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance spectroscopy of patients revealed altered energy metabolism, we considered a role for mitochondrial dysfunction. Studies of SCA7 mice uncovered marked impairments in oxygen consumption and respiratory exchange. When we examined cerebellar Purkinje cells in mice, we observed mitochondrial network abnormalities, with enlarged mitochondria upon ultrastructural analysis. We developed stem cell models from patients and created stem cell knockout rescue systems, documenting mitochondrial morphology defects, impaired oxidative metabolism, and reduced expression of nicotinamide adenine dinucleotide (NAD+) production enzymes in SCA7 models. We observed NAD+ reductions in mitochondria of SCA7 patient NPCs using ratiometric fluorescent sensors and documented alterations in tryptophan-kynurenine metabolism in patients. Our results indicate that mitochondrial dysfunction, stemming from decreased NAD+, is a defining feature of SCA7.	Adipose Tissue;Animals;Ataxin-7;Blood Glucose;Energy Metabolism;Humans;Kynurenine;Metabolomics;Mice;Mitochondria;Mitochondrial Diseases;NAD;Neural Stem Cells;Organelles;Peptides;Phenotype;Purkinje Cells;Reproducibility of Results;Spinocerebellar Ataxias;Trinucleotide Repeat Expansion;Tryptophan	Adipose Tissue;Animals;Ataxin-7;Blood Glucose;Energy Metabolism;Enzymes;Genes;Humans;Induced Pluripotent Stem Cells;Kynurenine;Magnetic Resonance Spectroscopy;Metabolism;Metabolomics;Mice;Mitochondria;Mitochondrial Diseases;NAD;Neural Stem Cells;Organelles;Oxygen Consumption;Patients;Peptides;Phenotype;Production;Purkinje Cells;Reproducibility of Results;Retinaldehyde;Role;Spinocerebellar Ataxia Type 7;Spinocerebellar Ataxias;Stem Cells;Trinucleotide Repeat Expansion;Trinucleotide Repeats;Tryptophan	Purkinje cell;ataxin-7;induced pluripotent stem cells;mitochondria;mouse model;nicotinamide adenine dinucleotide;oxidative metabolism;polyglutamine;spinocerebellar ataxia;trinucleotide repeat	Ward, Jacqueline M;Stoyas, Colleen A;Switonski, Pawel M;Ichou, Farid;Fan, Weiwei;Collins, Brett;Wall, Christopher E;Adanyeguh, Isaac;Niu, Chenchen;Sopher, Bryce L;Kinoshita, Chizuru;Morrison, Richard S;Durr, Alexandra;Muotri, Alysson R;Evans, Ronald M;Mochel, Fanny;La Spada, Albert R	[University of California, San Diego];[Duke University School of Medicine];[Duke University School of Medicine, Polish Academy of Sciences];[Institute of Cardiometabolism and Nutrition (France)];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Inserm, National Center for Scientific Research (France), Sorbonne University];[Duke University School of Medicine];[University of Washington];[University of Washington];[University of Washington];[Assistance Publique - Hôpitaux de Paris, Inserm, National Center for Scientific Research (France), Pitié-Salpêtrière Hospital, Sorbonne University];[University of California, San Diego];[Howard Hughes Medical Institute, Institute of Cardiometabolism and Nutrition (France), Salk Institute for Biological Studies];[Assistance Publique - Hôpitaux de Paris, Inserm, National Center for Scientific Research (France), Pitié-Salpêtrière Hospital, Sorbonne University];[Duke University, Duke University School of Medicine, University of California, San Diego]	2.89	34	Cell reports	26	5	1189-1202.e6
U19MH107367	Group 2	Genomics			SRA::SRP164940					10.1038/s41398-018-0344-y	30655503	2019	Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.	SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5+/- cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5+/- animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5+/- adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.	Animals;Autism Spectrum Disorder;Behavior, Animal;Brain;Female;Genetic Predisposition to Disease;Haploinsufficiency;Heterozygote;Magnetic Resonance Imaging;Male;Methyltransferases;Mice;Mice, Knockout;Mutation;Neurons	Adult;Animals;Autism Spectrum Disorder;Autistic Disorder;Behavior;Behavior, Animal;Brain;Dates;Electrophysiology;Family;Female;Gene Expression;Genes;Genes, vif;Genetic Predisposition to Disease;Haploinsufficiency;Heterozygote;Histone Methyltransferases;Id;Immunohistochemistry;In Vitro;Intellectual Disability;Lead;Magnetic Resonance Imaging;Male;Methyltransferases;Mice;Mice, Knockout;Mutation;Neurons;RNA-Seq;Risk Factors;SET Domain;Social Interaction		Moore, Spencer M;Seidman, Jason S;Ellegood, Jacob;Gao, Richard;Savchenko, Alex;Troutman, Ty D;Abe, Yohei;Stender, Josh;Lee, Daehoon;Wang, Sicong;Voytek, Bradley;Lerch, Jason P;Suh, Hoonkyo;Glass, Christopher K;Muotri, Alysson R	[University of California, San Diego];[University of California, San Diego];[The Hospital for Sick Children];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Cleveland Clinic, Lerner Research Institute];[University of California, San Diego];[University of California, San Diego];[The Hospital for Sick Children, University of Toronto];[Cleveland Clinic, Lerner Research Institute];[University of California, San Diego];[Rady Children's Hospital, University of California, San Diego]	0.63	10	Translational psychiatry	9	1	24
U19MH107367	Group 2	Genomics				GSE124706				10.7554/eLife.37527	30730291	2019	Species-specific maturation profiles of human, chimpanzee and bonobo neural cells.	Comparative analyses of neuronal phenotypes in closely related species can shed light on neuronal changes occurring during evolution. The study of post-mortem brains of nonhuman primates (NHPs) has been limited and often does not recapitulate important species-specific developmental hallmarks. We utilize induced pluripotent stem cell (iPSC) technology to investigate the development of cortical pyramidal neurons following migration and maturation of cells grafted in the developing mouse cortex. Our results show differential migration patterns in human neural progenitor cells compared to those of chimpanzees and bonobos both in vitro and in vivo, suggesting heterochronic changes in human neurons. The strategy proposed here lays the groundwork for further comparative analyses between humans and NHPs and opens new avenues for understanding the differences in the neural underpinnings of cognition and neurological disease susceptibility between species.	Animals;Cell Differentiation;Cell Line;Cell Movement;Dendrites;Gene Expression Regulation;Humans;Induced Pluripotent Stem Cells;Neural Stem Cells;Neurons;Pan paniscus;Pan troglodytes;Species Specificity	Animals;Brain;Cell Differentiation;Cell Line;Cell Movement;Cells;Cognition;Comprehension;Dendrites;Developmental Biology;Disease Susceptibility;Gene Expression Regulation;Humans;In Vitro;Induced Pluripotent Stem Cells;Light;Mice;Neural Stem Cells;Neurons;News;Pan paniscus;Pan troglodytes;Phenotype;Primates;Pyramidal Cells;Species Specificity;Stem Cells;Technology	chimpanzee;developmental biology;evolution;human;neurodevelopment;neuronal function;neuroprogenitor migration;non human primate	Marchetto, Maria C;Hrvoj-Mihic, Branka;Kerman, Bilal E;Yu, Diana X;Vadodaria, Krishna C;Linker, Sara B;Narvaiza, Iñigo;Santos, Renata;Denli, Ahmet M;Mendes, Ana Pd;Oefner, Ruth;Cook, Jonathan;McHenry, Lauren;Grasmick, Jaeson M;Heard, Kelly;Fredlender, Callie;Randolph-Moore, Lynne;Kshirsagar, Rijul;Xenitopoulos, Rea;Chou, Grace;Hah, Nasun;Muotri, Alysson R;Padmanabhan, Krishnan;Semendeferi, Katerina;Gage, Fred H	[Salk Institute for Biological Studies];[University of California, San Diego];[Istanbul Medipol University];[Huntsman Cancer Institute];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Inserm, Paris Descartes University, Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Rady Children's Hospital, University of California, San Diego];[University of Rochester];[University of California, San Diego];[Salk Institute for Biological Studies]	2.69	42	eLife	8
U19MH107367	Group 2									10.1038/s41598-019-55132-8	31848365	2019	Tissue-type plasminogen activator-primed human iPSC-derived neural progenitor cells promote motor recovery after severe spinal cord injury.	The goal of stem cell therapy for spinal cord injury (SCI) is to restore motor function without exacerbating pain. Induced pluripotent stem cells (iPSC) may be administered by autologous transplantation, avoiding immunologic challenges. Identifying strategies to optimize iPSC-derived neural progenitor cells (hiNPC) for cell transplantation is an important objective. Herein, we report a method that takes advantage of the growth factor-like and anti-inflammatory activities of the fibrinolysis protease, tissue plasminogen activator tPA, without effects on hemostasis. We demonstrate that conditioning hiNPC with enzymatically-inactive tissue-type plasminogen activator (EI-tPA), prior to grafting into a T3 lesion site in a clinically relevant severe SCI model, significantly improves motor outcomes. EI-tPA-primed hiNPC grafted into lesion sites survived, differentiated, acquired markers of motor neuron maturation, and extended βIII-tubulin-positive axons several spinal segments below the lesion. Importantly, only SCI rats that received EI-tPA primed hiNPC demonstrated significantly improved motor function, without exacerbating pain. When hiNPC were treated with EI-tPA in culture, NMDA-R-dependent cell signaling was initiated, expression of genes associated with stemness (Nestin, Sox2) was regulated, and thrombin-induced cell death was prevented. EI-tPA emerges as a novel agent capable of improving the efficacy of stem cell therapy in SCI.	Animals;Cell Differentiation;Humans;Induced Pluripotent Stem Cells;Motor Neurons;Neural Stem Cells;Neurogenesis;Rats;Recovery of Function;Spinal Cord;Spinal Cord Injuries;Stem Cell Transplantation;Stem Cells;Tissue Plasminogen Activator	Animals;Anti-Inflammatory Agents;Axons;Cell Death;Cell Differentiation;Cell Transplantation;Culture;Fibrinolysis;Genes;Goals;Growth Factors;Hemostasis;Humans;Induced Pluripotent Stem Cells;Methods;Motor Neurons;N-Methylaspartate;Nestin;Neural Stem Cells;Neurogenesis;Pain;Peptide Hydrolases;Rats;Recovery of Function;Report;Signal Transduction;Spinal Cord;Spinal Cord Injuries;Stem Cell Transplantation;Stem Cells;Therapeutics;Thrombin;Tissue Plasminogen Activator;Transplantation, Autologous;Tubulin		Shiga, Yasuhiro;Shiga, Akina;Mesci, Pinar;Kwon, HyoJun;Brifault, Coralie;Kim, John H;Jeziorski, Jacob J;Nasamran, Chanond;Ohtori, Seiji;Muotri, Alysson R;Gonias, Steven L;Campana, Wendy M	[Chiba University, University of California, San Diego];[Chiba University];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Chiba University];[University of California, San Diego];[University of California, San Diego];[US Department of Veterans Affairs, University of California, San Diego]	0.31	4	Scientific reports	9	1	19291
U19MH107367	Group 2					GSE107895,GSE107867,GSE117776,GSE51264,GSE59288				10.1038/s41593-018-0287-x	30559470	2019	Widespread RNA editing dysregulation in brains from autistic individuals.	Transcriptomic analyses of postmortem brains have begun to elucidate molecular abnormalities in autism spectrum disorder (ASD). However, a crucial pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here we profiled global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of postmortem brains of people with ASD. We observed a global bias for hypoediting in ASD brains, which was shared across brain regions and involved many synaptic genes. We show that the Fragile X proteins FMRP and FXR1P interact with RNA-editing enzymes (ADAR proteins) and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA-editing alterations in ASD and Fragile X syndrome, establishing this as a molecular link between these related diseases. Our findings, which are corroborated across multiple data sets, including dup15q (genomic duplication of 15q11.2-13.1) cases associated with intellectual disability, highlight RNA-editing dysregulation in ASD and reveal new mechanisms underlying this disorder.	Adenosine Deaminase;Autistic Disorder;Brain;Fragile X Mental Retardation Protein;Gene Expression Profiling;Humans;Neurons;RNA Editing;RNA-Binding Proteins	Adenosine;Adenosine Deaminase;Autism Spectrum Disorder;Autistic Disorder;Bias;Brain;Dataset;Disease;Enzymes;Fragile X Mental Retardation Protein;Fragile X Syndrome;Gene Expression Profiling;Genes;Genome;Genomics;Humans;Inosine;Intellectual Disability;Neurons;News;Persons;Proteins;RNA Editing;RNA-Binding Proteins;Scales		Tran, Stephen S;Jun, Hyun-Ik;Bahn, Jae Hoon;Azghadi, Adel;Ramaswami, Gokul;Van Nostrand, Eric L;Nguyen, Thai B;Hsiao, Yun-Hua E;Lee, Changhoon;Pratt, Gabriel A;Martínez-Cerdeño, Verónica;Hagerman, Randi J;Yeo, Gene W;Geschwind, Daniel H;Xiao, Xinshu	[University of California, Los Angeles];[University of California, Los Angeles];[University of California, Los Angeles];[University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[University of California, San Diego];[University of California, San Diego];[University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[University of California, San Diego];[University of California, Davis];[University of California, Davis];[University of California, San Diego];[David Geffen School of Medicine, University of California, Los Angeles];[University of California, Los Angeles]	4.39	66	Nature neuroscience	22	1	25-36
U19MH107367	Group 2					GSE131847				10.1126/sciimmunol.aaz6894	32414833	2020	Early precursors and molecular determinants of tissue-resident memory CD8+ T lymphocytes revealed by single-cell RNA sequencing.	During an immune response to microbial infection, CD8+ T cells give rise to distinct classes of cellular progeny that coordinately mediate clearance of the pathogen and provide long-lasting protection against reinfection, including a subset of noncirculating tissue-resident memory (TRM) cells that mediate potent protection within nonlymphoid tissues. Here, we used single-cell RNA sequencing to examine the gene expression patterns of individual CD8+ T cells in the spleen and small intestine intraepithelial lymphocyte (siIEL) compartment throughout the course of their differentiation in response to viral infection. These analyses revealed previously unknown transcriptional heterogeneity within the siIEL CD8+ T cell population at several stages of differentiation, representing functionally distinct TRM cell subsets and a subset of TRM cell precursors within the tissue early in infection. Together, these findings may inform strategies to optimize CD8+ T cell responses to protect against microbial infection and cancer.	Animals;CD8-Positive T-Lymphocytes;Cell Differentiation;Female;HEK293 Cells;Humans;Male;Mice;Mice, Inbred C57BL;Mice, Transgenic;Sequence Analysis, RNA;Single-Cell Analysis	Animals;CD8-Positive T-Lymphocytes;Cancer;Cell Differentiation;Cells;Female;Gene Expression;HEK293 Cells;Humans;Immunity;Infections;Intestine, Small;Intraepithelial Lymphocytes;Male;Memory;Mice;Mice, Inbred C57BL;Mice, Transgenic;Population;Reinfection;Sequence Analysis, RNA;Sequence Determinations, RNA;Single-Cell Analysis;Spleen;T-Lymphocytes;Tissues;Virus Diseases		Kurd, Nadia S;He, Zhaoren;Louis, Tiani L;Milner, J Justin;Omilusik, Kyla D;Jin, Wenhao;Tsai, Matthew S;Widjaja, Christella E;Kanbar, Jad N;Olvera, Jocelyn G;Tysl, Tiffani;Quezada, Lauren K;Boland, Brigid S;Huang, Wendy J;Murre, Cornelis;Goldrath, Ananda W;Yeo, Gene W;Chang, John T	[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego, VA San Diego Healthcare System]	4.48	51	Science immunology	5	47
U19MH107367	Group 2					GSE125527				10.1126/sciimmunol.abb4432	32826341	2020	Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses.	Inflammatory bowel disease (IBD) encompasses a spectrum of gastrointestinal disorders driven by dysregulated immune responses against gut microbiota. We integrated single-cell RNA and antigen receptor sequencing to elucidate key components, cellular states, and clonal relationships of the peripheral and gastrointestinal mucosal immune systems in health and ulcerative colitis (UC). UC was associated with an increase in IgG1+ plasma cells in colonic tissue, increased colonic regulatory T cells characterized by elevated expression of the transcription factor ZEB2, and an enrichment of a γδ T cell subset in the peripheral blood. Moreover, we observed heterogeneity in CD8+ tissue-resident memory T (TRM) cells in colonic tissue, with four transcriptionally distinct states of differentiation observed across health and disease. In the setting of UC, there was a marked shift of clonally related CD8+ TRM cells toward an inflammatory state, mediated, in part, by increased expression of the T-box transcription factor Eomesodermin. Together, these results provide a detailed atlas of transcriptional changes occurring in adaptive immune cells in the context of UC and suggest a role for CD8+ TRM cells in IBD.	Adaptive Immunity;Animals;Colitis, Ulcerative;Colon;Humans;Immunoglobulin G;Intraepithelial Lymphocytes;Male;Memory T Cells;Mice, Transgenic;Single-Cell Analysis;T-Lymphocytes, Regulatory	Adaptive Immunity;Animals;Atlas;Blood;Cells;Colitis, Ulcerative;Colon;Disease;Gastrointestinal Diseases;Gastrointestinal Microbiome;Health;Humans;IgG1;Immune System;Immunity;Immunoglobulin G;Inflammatory Bowel Diseases;Intraepithelial Lymphocytes;Male;Memory;Mice, Transgenic;Plasma Cells;RNA;Receptors, Antigen;Role;Single-Cell Analysis;T-Lymphocyte Subsets;T-Lymphocytes;T-Lymphocytes, Regulatory;Tissues;Transcription Factors;Zinc Finger E-box Binding Homeobox 2		Boland, Brigid S;He, Zhaoren;Tsai, Matthew S;Olvera, Jocelyn G;Omilusik, Kyla D;Duong, Han G;Kim, Eleanor S;Limary, Abigail E;Jin, Wenhao;Milner, J Justin;Yu, Bingfei;Patel, Shefali A;Louis, Tiani L;Tysl, Tiffani;Kurd, Nadia S;Bortnick, Alexandra;Quezada, Lauren K;Kanbar, Jad N;Miralles, Ara;Huylebroeck, Danny;Valasek, Mark A;Dulai, Parambir S;Singh, Siddharth;Lu, Li-Fan;Bui, Jack D;Murre, Cornelis;Sandborn, William J;Goldrath, Ananda W;Yeo, Gene W;Chang, John T	[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Erasmus Medical Center, KU Leuven];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego, VA San Diego Healthcare System]	2.97	28	Science immunology	5	50
U19MH107367	Group 2	Genomics				GSE117294				10.1038/s41594-020-0477-6	32807991	2020	Large-scale tethered function assays identify factors that regulate mRNA stability and translation.	The molecular functions of the majority of RNA-binding proteins (RBPs) remain unclear, highlighting a major bottleneck to a full understanding of gene expression regulation. Here, we develop a plasmid resource of 690 human RBPs that we subject to luciferase-based 3'-untranslated-region tethered function assays to pinpoint RBPs that regulate RNA stability or translation. Enhanced UV-cross-linking and immunoprecipitation of these RBPs identifies thousands of endogenous mRNA targets that respond to changes in RBP level, recapitulating effects observed in tethered function assays. Among these RBPs, the ubiquitin-associated protein 2-like (UBAP2L) protein interacts with RNA via its RGG domain and cross-links to mRNA and rRNA. Fusion of UBAP2L to RNA-targeting CRISPR-Cas9 demonstrates programmable translational enhancement. Polysome profiling indicates that UBAP2L promotes translation of target mRNAs, particularly global regulators of translation. Our tethering survey allows rapid assignment of the molecular activity of proteins, such as UBAP2L, to specific steps of mRNA metabolism.	3' Untranslated Regions;Binding Sites;CRISPR-Cas Systems;Carrier Proteins;Cell Line;Humans;Luciferases;Open Reading Frames;Polyribosomes;Protein Biosynthesis;RNA Stability;RNA-Binding Proteins;Recombinant Proteins;Ultraviolet Rays	3' Untranslated Regions;Binding Sites;CRISPR-Cas Systems;Carrier Proteins;Cell Line;Clustered Regularly Interspaced Short Palindromic Repeats;Comprehension;Gene Expression Regulation;Humans;Immunoprecipitation;Luciferases;Metabolism;Open Reading Frames;Plasmids;Polyribosomes;Protein Biosynthesis;Proteins;RNA;RNA Stability;RNA, Messenger;RNA-Binding Proteins;Recombinant Proteins;Resources;Scales;Surveys;Translations;Ubiquitin;Ultraviolet Rays;mRNA Stability		Luo, En-Ching;Nathanson, Jason L;Tan, Frederick E;Schwartz, Joshua L;Schmok, Jonathan C;Shankar, Archana;Markmiller, Sebastian;Yee, Brian A;Sathe, Shashank;Pratt, Gabriel A;Scaletta, Duy B;Ha, Yuanchi;Hill, David E;Aigner, Stefan;Yeo, Gene W	[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Dana-Farber Cancer Institute];[University of California, San Diego];[University of California, San Diego]	1.67	16	Nature structural & molecular biology	27	10	989-1000
U19MH107367	Group 2									10.1038/s41556-019-0454-7	32015437	2020	RNA-targeting CRISPR systems from metagenomic discovery to transcriptomic engineering.	Deployment of RNA-guided DNA endonuclease CRISPR-Cas technology has led to radical advances in biology. As the functional diversity of CRISPR-Cas and parallel systems is further explored, RNA manipulation is emerging as a powerful mode of CRISPR-based engineering. In this Perspective, we chart progress in the RNA-targeting CRISPR-Cas (RCas) field and illustrate how continuing evolution in scientific discovery translates into applications for RNA biology and insights into mysteries, obstacles, and alternative technologies that lie ahead.	Animals;Animals, Genetically Modified;CRISPR-Associated Protein 9;CRISPR-Cas Systems;Gene Editing;Genetic Engineering;Genetic Therapy;Humans;Metagenome;RNA, Guide;Transcriptome	Animals;Animals, Genetically Modified;Biology;CRISPR-Associated Protein 9;CRISPR-Cas Systems;Chart;Clustered Regularly Interspaced Short Palindromic Repeats;Deoxyribonuclease I;Engineering;Gene Editing;Genetic Engineering;Genetic Therapy;Humans;Metagenome;Metagenomics;RNA;RNA, Guide;Technology;Transcriptome		Smargon, Aaron A;Shi, Yilan J;Yeo, Gene W	[University of California, San Diego];[University of California, San Diego];[University of California, San Diego]	2.00	21	Nature cell biology	22	2	143-150
U19MH107367	Group 2					GSE147147				10.1038/s41422-020-0338-1	32499560	2020	Three-dimensional bioprinted glioblastoma microenvironments model cellular dependencies and immune interactions.	Brain tumors are dynamic complex ecosystems with multiple cell types. To model the brain tumor microenvironment in a reproducible and scalable system, we developed a rapid three-dimensional (3D) bioprinting method to construct clinically relevant biomimetic tissue models. In recurrent glioblastoma, macrophages/microglia prominently contribute to the tumor mass. To parse the function of macrophages in 3D, we compared the growth of glioblastoma stem cells (GSCs) alone or with astrocytes and neural precursor cells in a hyaluronic acid-rich hydrogel, with or without macrophage. Bioprinted constructs integrating macrophage recapitulate patient-derived transcriptional profiles predictive of patient survival, maintenance of stemness, invasion, and drug resistance. Whole-genome CRISPR screening with bioprinted complex systems identified unique molecular dependencies in GSCs, relative to sphere culture. Multicellular bioprinted models serve as a scalable and physiologic platform to interrogate drug sensitivity, cellular crosstalk, invasion, context-specific functional dependencies, as well as immunologic interactions in a species-matched neural environment.	Animals;Bioprinting;Cell Line, Tumor;Cell Proliferation;Glioblastoma;Humans;Mice;Neural Stem Cells;Tissue Scaffolds;Tumor Microenvironment	Animals;Astrocytes;Biomimetics;Bioprinting;Brain Neoplasms;Cell Line, Tumor;Cell Proliferation;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Culture;Drug Resistance;Ecosystem;Environment;Genome;Glioblastoma;Growth;Humans;Hyaluronic Acid;Hydrogels;Macrophages;Maintenance;Methods;Mice;Microglia;Neoplasms;Neural Stem Cells;Patients;Pharmaceutical Preparations;Relatives;Screening;Sensitivity;Stem Cells;Survival;Tissue Scaffolds;Tissues;Tumor Microenvironment		Tang, Min;Xie, Qi;Gimple, Ryan C;Zhong, Zheng;Tam, Trevor;Tian, Jing;Kidwell, Reilly L;Wu, Qiulian;Prager, Briana C;Qiu, Zhixin;Yu, Aaron;Zhu, Zhe;Mesci, Pinar;Jing, Hui;Schimelman, Jacob;Wang, Pengrui;Lee, Derrick;Lorenzini, Michael H;Dixit, Deobrat;Zhao, Linjie;Bhargava, Shruti;Miller, Tyler E;Wan, Xueyi;Tang, Jing;Sun, Bingjie;Cravatt, Benjamin F;Muotri, Alysson R;Chen, Shaochen;Rich, Jeremy N	[University of California, San Diego];[Institute for Advanced Study, Institute of Basic Medical Sciences, Beijing, University of California, San Diego, Westlake University];[Case Western Reserve University, University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Case Western Reserve University, Cleveland Clinic, Lerner Research Institute, University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Scripps Research];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Harvard Medical School, Massachusetts General Hospital];[University of California, San Diego];[Institute for Advanced Study, Institute of Basic Medical Sciences, Beijing, Westlake University];[University of California, San Diego];[Scripps Research];[Rady Children's Hospital, University of California, San Diego];[University of California, San Diego];[University of California, San Diego]	8.41	57	Cell research	30	10	833-853
U19MH107367	Group 2	Imaging								10.1128/JVI.02024-20	33328307	2020	Zika virus is transmitted in neural progenitor cells via cell-to-cell spread and infection is inhibited by the autophagy inducer trehalose.	Zika virus (ZIKV) is a mosquito-borne human pathogen that causes congenital Zika syndrome and neurological symptoms in some adults. There are currently no approved treatments or vaccines for ZIKV, and exploration of therapies targeting host processes could avoid viral development of drug resistance. The purpose of our study was to determine if the non-toxic and widely used disaccharide trehalose, which showed antiviral activity against Human Cytomegalovirus (HCMV) in our previous work, could restrict ZIKV infection in clinically relevant neural progenitor cells (NPCs). Trehalose is known to induce autophagy, the degradation and recycling of cellular components. Whether autophagy is proviral or antiviral for ZIKV is controversial and depends on cell type and specific conditions used to activate or inhibit autophagy. We show here that trehalose treatment of NPCs infected with recent ZIKV isolates from Panama and Puerto Rico significantly reduces viral replication and spread. In addition, we demonstrate that ZIKV infection in NPCs spreads primarily cell-to-cell as an expanding infectious center, and NPCs are infected via contact with infected cells far more efficiently than by cell-free virus. Importantly, ZIKV was able to spread in NPCs in the presence of neutralizing antibody.Importance Zika virus causes birth defects and can lead to neurological disease in adults. While infection rates are currently low, ZIKV remains a public health concern with no treatment or vaccine available. Targeting a cellular pathway to inhibit viral replication is a potential treatment strategy that avoids development of antiviral resistance. We demonstrate in this study that the non-toxic autophagy-inducing disaccharide trehalose reduces spread and output of ZIKV in infected neural progenitor cells (NPCs), the major cells infected in the fetus. We show that ZIKV spreads cell-to-cell in NPCs as an infectious center and that NPCs are more permissive to infection by contact with infected cells than by cell-free virus. We find that neutralizing antibody does not prevent the spread of the infection in NPCs. These results are significant in demonstrating anti-ZIKV activity of trehalose and in clarifying the primary means of Zika virus spread in clinically relevant target cells.		Adult;Antibodies, Neutralizing;Antiviral Agents;Autophagy;Cells;Congenital Abnormalities;Congenital Zika Syndrome;Culicidae;Cytomegalovirus;Disaccharides;Disease;Drug Resistance;Fetus;Humans;Infections;Lead;Panama;Public Health;Puerto Rico;Recycling;Stem Cells;Therapeutics;Trehalose;Vaccines;Virus Replication;Viruses;Work;Zika Virus		Clark, Alex E;Zhu, Zhe;Krach, Florian;Rich, Jeremy N;Yeo, Gene W;Spector, Deborah H	[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego]	0.10	1	Journal of virology
U19MH107367	Group 2	Genomics				GSE160146				10.15252/emmm.202012523	33501759	2021	Pharmacological reversal of synaptic and network pathology in human MECP2-KO neurons and cortical organoids.	Duplication or deficiency of the X-linked MECP2 gene reliably produces profound neurodevelopmental impairment. MECP2 mutations are almost universally responsible for Rett syndrome (RTT), and particular mutations and cellular mosaicism of MECP2 may underlie the spectrum of RTT symptomatic severity. No clinically approved treatments for RTT are currently available, but human pluripotent stem cell technology offers a platform to identify neuropathology and test candidate therapeutics. Using a strategic series of increasingly complex human stem cell-derived technologies, including human neurons, MECP2-mosaic neurospheres to model RTT female brain mosaicism, and cortical organoids, we identified synaptic dysregulation downstream from knockout of MECP2 and screened select pharmacological compounds for their ability to treat this dysfunction. Two lead compounds, Nefiracetam and PHA 543613, specifically reversed MECP2-knockout cytologic neuropathology. The capacity of these compounds to reverse neuropathologic phenotypes and networks in human models supports clinical studies for neurodevelopmental disorders in which MeCP2 deficiency is the predominant etiology.	Bridged Bicyclo Compounds, Heterocyclic;Female;Gene Knockout Techniques;Humans;Methyl-CpG-Binding Protein 2;Neurons;Organoids;Phenotype;Pyrrolidinones;Quinuclidines;Rett Syndrome	Ability;Brain;Bridged Bicyclo Compounds, Heterocyclic;Clinical Study;Disease;Drug Discovery;Female;Gene Knockout Techniques;Genes;Humans;Lead;Methyl-CpG-Binding Protein 2;Mosaicism;Mutation;Neurodevelopmental Disorders;Neurons;Neuropathology;Organoids;Pathology;Phenotype;Pluripotent Stem Cells;Pyrrolidinones;Quinuclidines;Rett Syndrome;Stem Cells;Technology;Therapeutics	MECP2 mosaicism;cortical organoids;drug discovery;neurodevelopmental disease modeling;stem cells	Trujillo, Cleber A;Adams, Jason W;Negraes, Priscilla D;Carromeu, Cassiano;Tejwani, Leon;Acab, Allan;Tsuda, Ben;Thomas, Charles A;Sodhi, Neha;Fichter, Katherine M;Romero, Sarah;Zanella, Fabian;Sejnowski, Terrence J;Ulrich, Henning;Muotri, Alysson R	[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];[Salk Institute for Biological Studies, University of California, San Diego];[Rady Children's Hospital, University of California, San Diego];;;;;[Salk Institute for Biological Studies, University of California, San Diego];[University of São Paulo];[Rady Children's Hospital, University of California, San Diego]	4.31	14	EMBO molecular medicine	13	1	e12523
U19MH107367	Group 2									10.1126/science.aax2537	33574182	2021	Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment.	The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 (NOVA1) plays a key role in neural development and function. NOVA1 also includes a protein-coding difference between the modern human genome and Neanderthal and Denisovan genomes. To investigate the functional importance of an amino acid change in humans, we reintroduced the archaic allele into human induced pluripotent cells using genome editing and then followed their neural development through cortical organoids. This modification promoted slower development and higher surface complexity in cortical organoids with the archaic version of NOVA1 Moreover, levels of synaptic markers and synaptic protein coassociations correlated with altered electrophysiological properties in organoids expressing the archaic variant. Our results suggest that the human-specific substitution in NOVA1, which is exclusive to modern humans since divergence from Neanderthals, may have had functional consequences for our species' evolution.	Alleles;Alternative Splicing;Amino Acid Substitution;Animals;Binding Sites;Biological Evolution;CRISPR-Cas Systems;Cell Proliferation;Cerebral Cortex;Gene Expression Regulation, Developmental;Genetic Variation;Genome;Genome, Human;Haplotypes;Hominidae;Humans;Induced Pluripotent Stem Cells;Neanderthals;Nerve Net;Nerve Tissue Proteins;Neuro-Oncological Ventral Antigen;Neurons;Organoids;RNA-Binding Proteins;Synapses	Alleles;Alternative Splicing;Amino Acid Substitution;Amino Acids;Animals;Antigens;Binding Sites;Biological Evolution;CRISPR-Cas Systems;Cell Proliferation;Cells;Cerebral Cortex;Coding;Gene Expression Regulation, Developmental;Genetic Variation;Genome;Genome Editing;Genome, Human;Haplotypes;Hominidae;Humans;Induced Pluripotent Stem Cells;Neanderthals;Nerve Net;Nerve Tissue Proteins;Neurons;Organoids;Play;Proteins;RNA-Binding Proteins;Role;Synapses		Trujillo, Cleber A;Rice, Edward S;Schaefer, Nathan K;Chaim, Isaac A;Wheeler, Emily C;Madrigal, Assael A;Buchanan, Justin;Preissl, Sebastian;Wang, Allen;Negraes, Priscilla D;Szeto, Ryan A;Herai, Roberto H;Huseynov, Alik;Ferraz, Mariana S A;Borges, Fernando S;Kihara, Alexandre H;Byrne, Ashley;Marin, Maximillian;Vollmers, Christopher;Brooks, Angela N;Lautz, Jonathan D;Semendeferi, Katerina;Shapiro, Beth;Yeo, Gene W;Smith, Stephen E P;Green, Richard E;Muotri, Alysson R	[University of California, San Diego];[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Epigenomics, Molecular Medicine Center (Bulgaria), University of California, San Diego];[Epigenomics, Molecular Medicine Center (Bulgaria), University of California, San Diego];[Epigenomics, Molecular Medicine Center (Bulgaria), University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Pontifical Catholic University of Paraná];[Imperial College London];[Federal University of ABC];[Federal University of ABC];[Federal University of ABC];[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, Santa Cruz];[Center for Integrative Brain Research Seattle, Children's National Medical Center, University of Washington];[University of California, San Diego];[Howard Hughes Medical Institute, University of California, Santa Cruz];[Epigenomics, Molecular Medicine Center (Bulgaria), University of California, San Diego];[Center for Integrative Brain Research Seattle, Children's National Medical Center, University of Washington];[University of California, Santa Cruz];[University of California, San Diego]	6.48	23	Science (New York, N.Y.)	371	6530
U19MH107367;U19MH106434	Group 2; Group 3									10.1038/nature19067	27509850	2016	A human neurodevelopmental model for Williams syndrome.	Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.	Adolescent;Adult;Apoptosis;Brain;Calcium;Cell Differentiation;Cell Shape;Cellular Reprogramming;Cerebral Cortex;Chromosomes, Human, Pair 7;Dendrites;Female;Frizzled Receptors;Haploinsufficiency;Humans;Induced Pluripotent Stem Cells;Male;Models, Neurological;Neural Stem Cells;Neurons;Phenotype;Reproducibility of Results;Synapses;Williams Syndrome;Young Adult	Ability;Adolescent;Adult;Apoptosis;Brain;Calcium;Calcium Waves;Cell Biology;Cell Differentiation;Cell Shape;Cellular Reprogramming;Cerebral Cortex;Chromosomes;Chromosomes, Human, Pair 7;Dendrites;Female;Frizzled Receptors;Genes;Genetics;Haploinsufficiency;Human Induced Pluripotent Stem Cells;Human Remains;Humans;Induced Pluripotent Stem Cells;Knowledge;Lead;Linguistics;Male;Models, Neurological;Neural Stem Cells;Neurodevelopmental Disorders;Neurons;Pathology;Phenotype;Reproducibility of Results;Spine;Staining;Stem Cells;Synapses;Time;Williams Syndrome;Young Adult		Chailangkarn, Thanathom;Trujillo, Cleber A;Freitas, Beatriz C;Hrvoj-Mihic, Branka;Herai, Roberto H;Yu, Diana X;Brown, Timothy T;Marchetto, Maria C;Bardy, Cedric;McHenry, Lauren;Stefanacci, Lisa;Järvinen, Anna;Searcy, Yvonne M;DeWitt, Michelle;Wong, Wenny;Lai, Philip;Ard, M Colin;Hanson, Kari L;Romero, Sarah;Jacobs, Bob;Dale, Anders M;Dai, Li;Korenberg, Julie R;Gage, Fred H;Bellugi, Ursula;Halgren, Eric;Semendeferi, Katerina;Muotri, Alysson R	;;;;;;;;;;;;;;;;;;;;;;;;;;;	4.24	103	Nature	536	7616	338-43
U19MH106434	Group 3									10.1016/j.neuron.2015.03.051	25856479	2015	Seeking a roadmap toward neuroepigenetics.	A group of papers investigates functional regulatory elements in genomes from human tissue samples and cell lines. What can neuroscientists learn from the gigantic data set and how will it affect the direction of neuroepigenetics?	Animals;Epigenomics;Genetics;Humans;Nervous System;Neurons	Affect;Animals;Cell Line;Dataset;Elements;Epigenomics;Genetics;Genome;Humans;Nervous System;Neurons;Paper;Tissues		Shin, Jaehoon;Ming, Guo-li;Song, Hongjun	[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins Medicine, Johns Hopkins School of Medicine]	0.13	4	Neuron	86	1	12-5
U19MH106434	Group 3	Review								10.1016/j.stem.2016.11.014	27912090	2016	Advances in Zika Virus Research: Stem Cell Models, Challenges, and Opportunities.	The re-emergence of Zika virus (ZIKV) and its suspected link with various disorders in newborns and adults led the World Health Organization to declare a global health emergency. In response, the stem cell field quickly established platforms for modeling ZIKV exposure using human pluripotent stem cell-derived neural progenitors and brain organoids, fetal tissues, and animal models. These efforts provided significant insight into cellular targets, pathogenesis, and underlying biological mechanisms of ZIKV infection as well as platforms for drug testing. Here we review the remarkable progress in stem cell-based ZIKV research and discuss current challenges and future opportunities.	Animals;Humans;Models, Biological;Nervous System;Stem Cell Research;Stem Cells;Zika Virus;Zika Virus Infection	Adult;Animals;Biopharmaceuticals;Brain;Cells;Emergencies;Fetal Tissue;Future;Global Health;Humans;Infant, Newborn;Infections;Microcephaly;Models, Animal;Models, Biological;Nervous System;Neurogenesis;Organoids;Pharmaceutical Preparations;Pluripotent Stem Cells;Radial Glial Cells;Research;Review;Stem Cell Research;Stem Cells;World Health Organization;Zika Virus;Zika Virus Infection	SpinΩ;Zika;iPSC;microcephaly;neurogenesis;organoid;outer radial glia cell;radial glia cell	Ming, Guo-Li;Tang, Hengli;Song, Hongjun	[Johns Hopkins Medicine, Johns Hopkins School of Medicine];[Florida State University];[Johns Hopkins Medicine, Johns Hopkins School of Medicine]	3.22	80	Cell stem cell	19	6	690-702
U19MH106434	Group 3									10.1038/nm.4184	27571349	2016	Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.	In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.	Astrocytes;Brain;Caspase 3;Caspase Inhibitors;Cell Death;Cell Line;Drug Repositioning;Humans;Induced Pluripotent Stem Cells;Microcephaly;Neural Stem Cells;Neurons;Niclosamide;Organoids;Pentanoic Acids;Virus Replication;Zika Virus;Zika Virus Infection	Anthelmintics;Antiviral Agents;Astrocytes;Brain;Caspase 3;Caspase Inhibitors;Cell Death;Cell Line;Cells;Clinical Trial;Culture;Cyclin-Dependent Kinases;Disease Outbreaks;Drug Development;Drug Repositioning;Emergencies;Global Health;Humans;Induced Pluripotent Stem Cells;Infections;Lead;Microcephaly;Neural Stem Cells;Neurons;Niclosamide;Organoids;Pentanoic Acids;Pharmaceutical Preparations;Screening;Therapeutics;United States Food and Drug Administration;Virus Replication;Zika Virus;Zika Virus Infection		Xu, Miao;Lee, Emily M;Wen, Zhexing;Cheng, Yichen;Huang, Wei-Kai;Qian, Xuyu;Tcw, Julia;Kouznetsova, Jennifer;Ogden, Sarah C;Hammack, Christy;Jacob, Fadi;Nguyen, Ha Nam;Itkin, Misha;Hanna, Catherine;Shinn, Paul;Allen, Chase;Michael, Samuel G;Simeonov, Anton;Huang, Wenwei;Christian, Kimberly M;Goate, Alison;Brennand, Kristen J;Huang, Ruili;Xia, Menghang;Ming, Guo-Li;Zheng, Wei;Song, Hongjun;Tang, Hengli	[National Center for Advancing Translational Sciences, National Institutes of Health, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine];[Florida State University];[Emory University School of Medicine, Johns Hopkins School of Medicine];[Florida State University];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Icahn School of Medicine];[National Center for Advancing Translational Sciences, National Institutes of Health];[Florida State University];[Florida State University];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[National Center for Advancing Translational Sciences, National Institutes of Health];[Florida State University];[National Center for Advancing Translational Sciences, National Institutes of Health];[Florida State University];[National Center for Advancing Translational Sciences, National Institutes of Health];[National Center for Advancing Translational Sciences, National Institutes of Health];[National Center for Advancing Translational Sciences, National Institutes of Health];[Johns Hopkins School of Medicine];[Icahn School of Medicine];[Icahn School of Medicine];[National Center for Advancing Translational Sciences, National Institutes of Health];[National Center for Advancing Translational Sciences, National Institutes of Health];[Johns Hopkins School of Medicine];[National Center for Advancing Translational Sciences, National Institutes of Health];[Johns Hopkins School of Medicine];[Florida State University]	19.79	417	Nature medicine	22	10	1101-1107
U19MH106434	Group 3	Review								10.1523/JNEUROSCI.2492-16.2016	27911745	2016	The Role of Epigenetic Mechanisms in the Regulation of Gene Expression in the Nervous System.	Neuroepigenetics is a newly emerging field in neurobiology that addresses the epigenetic mechanism of gene expression regulation in various postmitotic neurons, both over time and in response to environmental stimuli. In addition to its fundamental contribution to our understanding of basic neuronal physiology, alterations in these neuroepigenetic mechanisms have been recently linked to numerous neurodevelopmental, psychiatric, and neurodegenerative disorders. This article provides a selective review of the role of DNA and histone modifications in neuronal signal-induced gene expression regulation, plasticity, and survival and how targeting these mechanisms could advance the development of future therapies. In addition, we discuss a recent discovery on how double-strand breaks of genomic DNA mediate the rapid induction of activity-dependent gene expression in neurons.	Animals;Brain;Epigenesis, Genetic;Gene Expression Regulation, Developmental;Humans;Models, Genetic;Nerve Tissue Proteins;Neurons	Address;Animals;Brain;Comprehension;DNA;DNA Methylation;DNA Topoisomerases, Type II;Epigenesis, Genetic;Epigenetics;Future;Gene Expression;Gene Expression Regulation;Gene Expression Regulation, Developmental;Genomics;Histone Code;Humans;Models, Genetic;Nerve Tissue Proteins;Nervous System;Neurobiology;Neurodegenerative Diseases;Neurons;Physiology;Review;Role;Survival;Therapeutics;Time	DNA double strand breaks;DNA methylation;MeCP2;polycomb repressive complex;topoisomerase II	Cholewa-Waclaw, Justyna;Bird, Adrian;von Schimmelmann, Melanie;Schaefer, Anne;Yu, Huimei;Song, Hongjun;Madabhushi, Ram;Tsai, Li-Huei	[University of Edinburgh, Wellcome Trust];[University of Edinburgh, Wellcome Trust];[Icahn School of Medicine];[Icahn School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Massachusetts Institute of Technology];[Massachusetts Institute of Technology]	2.98	72	The Journal of neuroscience : the official journal of the Society for Neuroscience	36	45	11427-11434
U19MH106434	Group 3									10.1007/s40473-016-0100-7	28191386	2016	Using Induced Pluripotent Stem Cells to Investigate Complex Genetic Psychiatric Disorders.	Induced pluripotent stem cells (iPSCs) can be generated from human patient tissue samples, differentiated into any somatic cell type, and studied under controlled culture conditions. We review how iPSCs are used to investigate genetic factors and biological mechanisms underlying psychiatric disorders, and considerations for synthesizing data across studies. Results from patient specific-iPSC studies often reveal cellular phenotypes consistent with postmortem and brain imaging studies. Unpredicted findings illustrate the power of iPSCs as a discovery tool, but may also be attributable to limitations in modeling dynamic neural networks or difficulty in identifying the most affected neural subtype or developmental stage. Technological advances in differentiation protocols and organoid generation will enhance our ability to model the salient pathology underlying psychiatric disorders using iPSCs. The field will also benefit from context-driven interpretations of iPSC studies that recognize all potential sources of variability, including differences in patient symptomatology, genetic risk factors and affected cellular subtype.		Ability;Autism Spectrum Disorder;Biopharmaceuticals;Bipolar Disorder;Brain Imaging;Cells;Cellular Reprogramming;Culture;Generations;Genetics;Humans;Induced Pluripotent Stem Cells;Mental Disorders;Organoids;Pathology;Patients;Phenotype;Power, Psychological;Review;Risk Factors;Schizophrenia;Tissues	autism spectrum disorders;bipolar disorder;cellular reprogramming;iPSCs;psychiatric;schizophrenia	Temme, Stephanie J;Maher, Brady J;Christian, Kimberly M	[Johns Hopkins School of Medicine, Lieber Institute for Brain Development];[Johns Hopkins School of Medicine, Lieber Institute for Brain Development];[Johns Hopkins School of Medicine]	0.18	5	Current behavioral neuroscience reports	3	4	275-284
U19MH106434	Group 3									10.1016/j.neuron.2017.10.010	29103808	2017	DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis.	Mutations of DISC1 (disrupted-in-schizophrenia 1) have been associated with major psychiatric disorders. Despite the hundreds of DISC1-binding proteins reported, almost nothing is known about how DISC1 interacts with other proteins structurally to impact human brain development. Here we solved the high-resolution structure of DISC1 C-terminal tail in complex with its binding domain of Ndel1. Mechanistically, DISC1 regulates Ndel1's kinetochore attachment, but not its centrosome localization, during mitosis. Functionally, disrupting DISC1/Ndel1 complex formation prolongs mitotic length and interferes with cell-cycle progression in human cells, and it causes cell-cycle deficits of radial glial cells in the embryonic mouse cortex and human forebrain organoids. We also observed similar deficits in organoids derived from schizophrenia patient induced pluripotent stem cells (iPSCs) with a DISC1 mutation that disrupts its interaction with Ndel1. Our study uncovers a new mechanism of action for DISC1 based on its structure, and it has implications for how genetic insults may contribute to psychiatric disorders.	Animals;Carrier Proteins;Cell Cycle;Female;HeLa Cells;Humans;Immunohistochemistry;Male;Mice;Mitosis;Models, Molecular;Nerve Tissue Proteins;Neural Stem Cells;Neurogenesis;Neurons;Pluripotent Stem Cells;Pregnancy;Protein Binding;Schizophrenia	Animals;Binding Proteins;Brain;Carrier Proteins;Cell Cycle;Cells;Centrosome;Female;Genetics;HeLa Cells;Humans;Immunohistochemistry;Induced Pluripotent Stem Cells;Kinetochores;Male;Mental Disorders;Mice;Mitosis;Models, Molecular;Mutation;Nerve Tissue Proteins;Neural Stem Cells;Neurogenesis;Neurons;News;Organoids;Patients;Pluripotent Stem Cells;Pregnancy;Prosencephalon;Proteins;Radial Glial Cells;Schizophrenia;Tail	DISC1;NDE1;NDEL1;cell cycle;complex structure;human forebrain organoid;kinetochore attachment;neurogenesis;psychiatric disorders	Ye, Fei;Kang, Eunchai;Yu, Chuan;Qian, Xuyu;Jacob, Fadi;Yu, Cong;Mao, Mao;Poon, Randy Y C;Kim, Jieun;Song, Hongjun;Ming, Guo-Li;Zhang, Mingjie	[Hong Kong University of Science and Technology];[Johns Hopkins School of Medicine, University of Pennsylvania];[Hong Kong University of Science and Technology];[Johns Hopkins School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine, University of Pennsylvania];[Hong Kong University of Science and Technology];[Hong Kong University of Science and Technology];[Hong Kong University of Science and Technology];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine, University of Pennsylvania];[Hong Kong University of Science and Technology]	3.06	66	Neuron	96	5	1041-1054.e5
U19MH106434	Group 3									10.1101/gad.298216.117	28566536	2017	How does Zika virus cause microcephaly?	The re-emergence of Zika virus (ZIKV), a mosquito-borne and sexually transmitted flavivirus circulating in >70 countries and territories, poses a significant global threat to public health due to its ability to cause severe developmental defects in the human brain, such as microcephaly. Since the World Health Organization declared the ZIKV outbreak a Public Health Emergency of International Concern, remarkable progress has been made to gain insight into cellular targets, pathogenesis, and underlying biological mechanisms of ZIKV infection. Here we review the current knowledge and progress in understanding the impact of ZIKV exposure on the mammalian brain development and discuss potential underlying mechanisms.	Animals;Disease Outbreaks;Humans;Microcephaly;Zika Virus;Zika Virus Infection	Ability;Animals;Biopharmaceuticals;Brain;Comprehension;Culicidae;Disease Outbreaks;Emergencies;Flavivirus;Humans;Infections;Knowledge;Microcephaly;Public Health;Review;World Health Organization;Zika Virus;Zika Virus Infection	Zika virus;brain development;microcephaly	Wen, Zhexing;Song, Hongjun;Ming, Guo-Li	[Emory University School of Medicine];[Johns Hopkins School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine, University of Pennsylvania]	4.01	72	Genes & development	31	9	849-861
U19MH106434	Group 3									10.1074/jbc.H117.796383	29196569	2017	Stem cells take the stairs.	Human embryonic stem cells progress through multiple stages in their path to neural differentiation, but the steps taken along the way are difficult to distinguish, limiting our understanding of this important process. Jing and colleagues (2) now report comprehensive analyses of transcriptome dynamics during this process that reveal five discrete stages, defined in part by highly connected transcription factor networks that link progressive stages. Surprisingly, the third stage, which appears to be critical for neural fate commitment, depends almost entirely on intracellular signaling.	Cell Differentiation;Embryonic Stem Cells;Humans;Sequence Analysis, RNA;Signal Transduction;Transcription Factors;Transcriptome	Cell Differentiation;Comprehension;Embryonic Stem Cells;Human Embryonic Stem Cells;Humans;Report;Sequence Analysis, RNA;Signal Transduction;Stem Cells;Transcription Factors;Transcriptome		Vissers, Caroline;Ming, Guo-Li;Song, Hongjun	[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine, University of Pennsylvania]	0.00	0	The Journal of biological chemistry	292	48	19605-19606
U19MH106434	Group 3	Genomics				GSE99017				10.1016/j.cell.2017.09.003	28965759	2017	Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation.	N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here, we show that m6A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m6A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m6A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m6A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m6A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m6A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m6A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.	Animals;Cell Cycle;Gene Expression Regulation;Gene Expression Regulation, Developmental;Gene Knockdown Techniques;Humans;Methylation;Methyltransferases;Mice;Mice, Knockout;Neural Stem Cells;Neurogenesis;Organoids;Prosencephalon;RNA Processing, Post-Transcriptional;RNA Stability;RNA, Messenger	Animals;Autistic Disorder;Brain;Brain Diseases;Cell Cycle;Cells;Gene Expression Regulation;Gene Expression Regulation, Developmental;Gene Knockdown Techniques;Genes;Humans;Lead;Maintenance;Methylation;Methyltransferases;Mice;Mice, Knockout;Neural Stem Cells;Neurogenesis;Organoids;Prosencephalon;RNA;RNA Processing, Post-Transcriptional;RNA Stability;RNA, Messenger;Radial Glial Cells;Risk;Schizophrenia;Transcription Factors	Mettl14;RNA methylation;autism;epitranscriptomics;human organoid;m(6)A;neurogenesis;radial glia cell;schizophrenia;transcriptional prepatterning	Yoon, Ki-Jun;Ringeling, Francisca Rojas;Vissers, Caroline;Jacob, Fadi;Pokrass, Michael;Jimenez-Cyrus, Dennisse;Su, Yijing;Kim, Nam-Shik;Zhu, Yunhua;Zheng, Lily;Kim, Sunghan;Wang, Xinyuan;Doré, Louis C;Jin, Peng;Regot, Sergi;Zhuang, Xiaoxi;Canzar, Stefan;He, Chuan;Ming, Guo-Li;Song, Hongjun	[Johns Hopkins School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[University of Pennsylvania];[Johns Hopkins School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[University of Pennsylvania];[Howard Hughes Medical Institute, University of Chicago];[Emory University];[Johns Hopkins School of Medicine];[University of Chicago];[Ludwig Maximilians University of Munich];[Howard Hughes Medical Institute, University of Chicago];[Johns Hopkins School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine, University of Pennsylvania]	13.92	321	Cell	171	4	877-889.e17
U19MH106434	Group 3									10.1242/dev.140707	28292840	2017	Using brain organoids to understand Zika virus-induced microcephaly.	Technologies to differentiate human pluripotent stem cells into three-dimensional organized structures that resemble in vivo organs are pushing the frontiers of human disease modeling and drug development. In response to the global health emergency posed by the Zika virus (ZIKV) outbreak, brain organoids engineered to mimic the developing human fetal brain have been employed to model ZIKV-induced microcephaly. Here, we discuss the advantages of brain organoids over other model systems to study development and highlight recent advances in understanding ZIKV pathophysiology and its underlying pathogenesis mechanisms. We further discuss perspectives on overcoming limitations of current organoid systems for their future use in ZIKV research.	Animals;Brain;Humans;Microcephaly;Organoids;Zika Virus;Zika Virus Infection	Animals;Brain;Comprehension;Disease;Disease Outbreaks;Drug Development;Emergencies;Future;Global Health;Humans;Microcephaly;Organoids;Pluripotent Stem Cells;Research;Technology;Zika Virus;Zika Virus Infection	Cortex;Microcephaly;Organoids;Zika;iPSC	Qian, Xuyu;Nguyen, Ha Nam;Jacob, Fadi;Song, Hongjun;Ming, Guo-Li	[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins Medicine, Johns Hopkins School of Medicine]	5.84	124	Development (Cambridge, England)	144	6	952-957
U19MH106434	Group 3					GSE87750				10.1038/nn.4612	28758997	2017	Zika virus directly infects peripheral neurons and induces cell death.	Zika virus (ZIKV) infection is associated with neurological disorders of both the CNS and peripheral nervous systems (PNS), yet few studies have directly examined PNS infection. Here we show that intraperitoneally or intraventricularly injected ZIKV in the mouse can infect and impact peripheral neurons in vivo. Moreover, ZIKV productively infects stem-cell-derived human neural crest cells and peripheral neurons in vitro, leading to increased cell death, transcriptional dysregulation and cell-type-specific molecular pathology.	Animals;Cell Death;Cells, Cultured;Chlorocebus aethiops;Humans;Mice;Mice, 129 Strain;Mice, Inbred ICR;Neural Stem Cells;Peripheral Nervous System Diseases;Vero Cells;Zika Virus;Zika Virus Infection	Animals;Cell Death;Cells;Cells, Cultured;Chlorocebus aethiops;Humans;In Vitro;Infections;Mice;Mice, 129 Strain;Mice, Inbred ICR;Nervous System Diseases;Neural Crest Cells;Neural Stem Cells;Neurons;Pathology, Molecular;Peripheral Nervous System;Peripheral Nervous System Diseases;Stem Cells;Vero Cells;Zika Virus;Zika Virus Infection		Oh, Yohan;Zhang, Feiran;Wang, Yaqing;Lee, Emily M;Choi, In Young;Lim, Hotae;Mirakhori, Fahimeh;Li, Ronghua;Huang, Luoxiu;Xu, Tianlei;Wu, Hao;Li, Cui;Qin, Cheng-Feng;Wen, Zhexing;Wu, Qing-Feng;Tang, Hengli;Xu, Zhiheng;Jin, Peng;Song, Hongjun;Ming, Guo-Li;Lee, Gabsang	[Johns Hopkins School of Medicine, Medical Research Foundation];[Emory University School of Medicine];[Chinese Academy of Sciences];[Florida State University];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Emory University School of Medicine];[Emory University School of Medicine];[Emory University];[Emory University, Rollins School of Public Health];[Chinese Academy of Sciences];[Beijing Institute of Microbiology and Epidemiology, State Key Laboratory of Pathogen and Biosecurity];[Emory University School of Medicine, Johns Hopkins School of Medicine];[Chinese Academy of Sciences];[Florida State University];[Beijing Institute of Technology, Chinese Academy of Sciences];[Emory University School of Medicine];[Johns Hopkins School of Medicine, Medical Research Foundation, University of Pennsylvania];[Johns Hopkins School of Medicine, Medical Research Foundation, University of Pennsylvania];[Johns Hopkins School of Medicine, Medical Research Foundation]	2.33	46	Nature neuroscience	20	9	1209-1212
U19MH106434	Group 3									10.1016/j.stem.2017.07.014	28826723	2017	Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins.	Zika virus (ZIKV) directly infects neural progenitors and impairs their proliferation. How ZIKV interacts with the host molecular machinery to impact neurogenesis in vivo is not well understood. Here, by systematically introducing individual proteins encoded by ZIKV into the embryonic mouse cortex, we show that expression of ZIKV-NS2A, but not Dengue virus (DENV)-NS2A, leads to reduced proliferation and premature differentiation of radial glial cells and aberrant positioning of newborn neurons. Mechanistically, in vitro mapping of protein-interactomes and biochemical analysis suggest interactions between ZIKA-NS2A and multiple adherens junction complex (AJ) components. Functionally, ZIKV-NS2A, but not DENV-NS2A, destabilizes the AJ complex, resulting in impaired AJ formation and aberrant radial glial fiber scaffolding in the embryonic mouse cortex. Similarly, ZIKA-NS2A, but not DENV-NS2A, reduces radial glial cell proliferation and causes AJ deficits in human forebrain organoids. Together, our results reveal pathogenic mechanisms underlying ZIKV infection in the developing mammalian brain.	Adherens Junctions;Animals;Cell Differentiation;Cell Proliferation;Cerebral Cortex;HEK293 Cells;Humans;Mammals;Membrane Proteins;Mice;Neurogenesis;Neuroglia;Protein Binding;Protein Interaction Mapping;Proteolysis;Viral Nonstructural Proteins;Zika Virus;Zika Virus Infection	Adherens Junctions;Animals;Binding Proteins;Brain;Cell Differentiation;Cell Proliferation;Cerebral Cortex;Dengue Virus;Flavivirus;HEK293 Cells;Humans;In Vitro;Infant, Newborn;Infections;Lead;Mammals;Membrane Proteins;Mice;Microcephaly;Neural Stem Cells;Neurogenesis;Neuroglia;Neurons;Organoids;Prosencephalon;Protein Interaction Mapping;Protein Microarrays;Proteins;Proteolysis;Radial Glial Cells;Viral Nonstructural Proteins;Zika Virus;Zika Virus Infection	Zika virus;adherens junction;cortical neurogenesis;flavivirus;human organoid;human protein microarray;microcephaly;neural stem cell;neuronal migration;radial glial cell	Yoon, Ki-Jun;Song, Guang;Qian, Xuyu;Pan, Jianbo;Xu, Dan;Rho, Hee-Sool;Kim, Nam-Shik;Habela, Christa;Zheng, Lily;Jacob, Fadi;Zhang, Feiran;Lee, Emily M;Huang, Wei-Kai;Ringeling, Francisca Rojas;Vissers, Caroline;Li, Cui;Yuan, Ling;Kang, Koeun;Kim, Sunghan;Yeo, Junghoon;Cheng, Yichen;Liu, Sheng;Wen, Zhexing;Qin, Cheng-Feng;Wu, Qingfeng;Christian, Kimberly M;Tang, Hengli;Jin, Peng;Xu, Zhiheng;Qian, Jiang;Zhu, Heng;Song, Hongjun;Ming, Guo-Li	[Johns Hopkins School of Medicine];[Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Chinese Academy of Sciences, Fuzhou University];[Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Emory University School of Medicine];[Florida State University];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Chinese Academy of Sciences];[Chinese Academy of Sciences];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Florida State University];[Johns Hopkins School of Medicine];[Emory University School of Medicine];[Beijing Institute of Microbiology and Epidemiology, State Key Laboratory of Pathogen and Biosecurity];[Chinese Academy of Sciences];[University of Pennsylvania];[Florida State University];[Emory University School of Medicine];[Chinese Academy of Sciences];[Johns Hopkins School of Medicine];[Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine, Perelman School of Medicine, University of Pennsylvania]	5.15	104	Cell stem cell	21	3	349-358.e6
U19MH106434	Group 3									10.1038/mp.2017.175	28924182	2018	An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis.	Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.	Brain;Cell Differentiation;Cell Movement;Cells, Cultured;Cerebral Cortex;Doublecortin Domain Proteins;Doublecortin Protein;Fibroblasts;Humans;Induced Pluripotent Stem Cells;Infant;Infant, Newborn;Lissencephaly;Male;Microtubule-Associated Proteins;Neural Stem Cells;Neurites;Neurogenesis;Neurons;Neuropeptides	Brain;Cell Differentiation;Cell Movement;Cells;Cells, Cultured;Cerebral Cortex;Disease;Dissection;Exhibition;Fibroblasts;Genes;Humans;In Vitro;Induced Pluripotent Stem Cells;Infant;Infant, Newborn;Knowledge;Lissencephalies, Classical;Lissencephaly;Male;Microtubule-Associated Proteins;Models, Animal;Mutation;Neural Stem Cells;Neurites;Neurogenesis;Neurons;Neuropeptides;Patients;Protein Domains;Proteins;Role;Seizures;Technology		Shahsavani, M;Pronk, R J;Falk, R;Lam, M;Moslem, M;Linker, S B;Salma, J;Day, K;Schuster, J;Anderlid, B-M;Dahl, N;Gage, F H;Falk, A	[Karolinska Institute];[Karolinska Institute];[Karolinska Institute];[Karolinska Institute];[Karolinska Institute];[Salk Institute for Biological Studies];[Karolinska Institute];[Karolinska Institute];[Uppsala University];[Karolinska University Hospital];[Uppsala University];[Salk Institute for Biological Studies];[Karolinska Institute]	1.56	24	Molecular psychiatry	23	7	1674-1684
U19MH106434	Group 3									10.1038/nbt.4127	29658944	2018	An in vivo model of functional and vascularized human brain organoids.	Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.	Animals;Blood Vessels;Brain;Cell Differentiation;Humans;Mice;Neurogenesis;Neurons;Organoids;Pluripotent Stem Cells;Transplants	Adult;Animals;Axons;Blood Vessels;Brain;Cell Differentiation;Disease;Environment;Growth;Humans;Methods;Mice;Microglia;Neurogenesis;Neurons;Optogenetics;Organoids;Photons;Pluripotent Stem Cells;Transplants		Mansour, Abed AlFatah;Gonçalves, J Tiago;Bloyd, Cooper W;Li, Hao;Fernandes, Sarah;Quang, Daphne;Johnston, Stephen;Parylak, Sarah L;Jin, Xin;Gage, Fred H	[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies, San Diego State University];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies]	26.02	420	Nature biotechnology	36	5	432-441
U19MH106434	Group 3	NA								10.1093/ije/dyx229	29211851	2018	Cohort Profile: The Heinz C. Prechter Longitudinal Study of Bipolar Disorder.		Adult;Age of Onset;Bipolar Disorder;Circadian Rhythm;Cognition Disorders;Computer Simulation;Diet;Early Diagnosis;Epidemiologic Methods;Female;Genome-Wide Association Study;Humans;Life Change Events;Male;Microbiota;Motivation;Personality;Phenotype;Risk Factors;Sex Factors;Sleep Wake Disorders	Adult;Age of Onset;Bipolar Disorder;Circadian Rhythm;Cognition Disorders;Computer Simulation;Diet;Early Diagnosis;Epidemiologic Methods;Female;Genome-Wide Association Study;Humans;Life Change Events;Longitudinal Studies;Male;Microbiota;Motivation;Personality;Phenotype;Risk Factors;Sex Factors;Sleep Wake Disorders		McInnis, Melvin G;Assari, Shervin;Kamali, Masoud;Ryan, Kelly;Langenecker, Scott A;Saunders, Erika F H;Versha, Kritika;Evans, Simon;O'Shea, K Sue;Mower Provost, Emily;Marshall, David;Forger, Daniel;Deldin, Patricia;Zoellner, Sebastian;	[University of Michigan, Ann Arbor];[University of Michigan, Ann Arbor];[Massachusetts General Hospital, University of Michigan, Ann Arbor];[University of Michigan, Ann Arbor];[University of Illinois, Chicago];[Pennsylvania State University];[University of Michigan, Ann Arbor];[University of Michigan, Ann Arbor];[University of Michigan, Ann Arbor];;[University of Michigan, Ann Arbor];;;[University of Michigan, Ann Arbor];	2.53	25	International journal of epidemiology	47	1	28-28n
U19MH106434	Group 3					GSE111977,GSE111978,GSE111979				10.1016/j.stem.2018.04.009	29727680	2018	Efficient Generation of CA3 Neurons from Human Pluripotent Stem Cells Enables Modeling of Hippocampal Connectivity In Vitro.	Despite widespread interest in using human induced pluripotent stem cells (hiPSCs) in neurological disease modeling, a suitable model system to study human neuronal connectivity is lacking. Here, we report a comprehensive and efficient differentiation paradigm for hiPSCs that generate multiple CA3 pyramidal neuron subtypes as detected by single-cell RNA sequencing (RNA-seq). This differentiation paradigm exhibits characteristics of neuronal network maturation, and rabies virus tracing revealed synaptic connections between stem cell-derived dentate gyrus (DG) and CA3 neurons in vitro recapitulating the neuronal connectivity within the hippocampus. Because hippocampal dysfunction has been implicated in schizophrenia, we applied DG and CA3 differentiation paradigms to schizophrenia-patient-derived hiPSCs. We detected reduced activity in DG-CA3 co-culture and deficits in spontaneous and evoked activity in CA3 neurons from schizophrenia-patient-derived hiPSCs. Our approach offers critical insights into the network activity aspects of schizophrenia and may serve as a promising tool for modeling diseases with hippocampal vulnerability. VIDEO ABSTRACT.	Adult;Animals;Cell Differentiation;Dentate Gyrus;Female;Hippocampus;Humans;Induced Pluripotent Stem Cells;Male;Mice;Mice, Inbred C57BL;Mice, Inbred NOD;Mice, SCID;Middle Aged;Neurons;Schizophrenia;Young Adult	Abstracts;Adult;Animals;Cell Differentiation;Cells;Coculture Techniques;Dentate Gyrus;Disease;Exhibition;Female;Generations;Hippocampus;Human Induced Pluripotent Stem Cells;Humans;In Vitro;Induced Pluripotent Stem Cells;Male;Mice;Mice, Inbred C57BL;Mice, Inbred NOD;Mice, SCID;Middle Aged;Neurons;Patients;Pluripotent Stem Cells;Pyramidal Cells;RNA-Seq;Rabies;Rabies virus;Report;Schizophrenia;Sequence Determinations, RNA;Stem Cells;Young Adult	CA3;DG;disease-in-a-dish;hippocampus;neuronal diversity;pyramidal neurons;rabies tracing;schizophrenia;single cell sequencing;synaptic connectivity	Sarkar, Anindita;Mei, Arianna;Paquola, Apua C M;Stern, Shani;Bardy, Cedric;Klug, Jason R;Kim, Stacy;Neshat, Neda;Kim, Hyung Joon;Ku, Manching;Shokhirev, Maxim N;Adamowicz, David H;Marchetto, Maria C;Jappelli, Roberto;Erwin, Jennifer A;Padmanabhan, Krishnan;Shtrahman, Matthew;Jin, Xin;Gage, Fred H	[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Johns Hopkins School of Medicine, Lieber Institute for Brain Development, Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Flinders University, Salk Institute for Biological Studies, South Australian Health and Medical Research Institute];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies, University of Nebraska Medical Center];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies, UC San Diego School of Medicine];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Johns Hopkins School of Medicine, Lieber Institute for Brain Development, Salk Institute for Biological Studies];[Salk Institute for Biological Studies, University of Rochester];[Salk Institute for Biological Studies, UC San Diego School of Medicine];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies]	3.32	58	Cell stem cell	22	5	684-697.e9
U19MH106434	Group 3									10.1083/jcb.201802117	29666150	2018	Epigenetics and epitranscriptomics in temporal patterning of cortical neural progenitor competence.	During embryonic brain development, neural progenitor/stem cells (NPCs) sequentially give rise to different subtypes of neurons and glia via a highly orchestrated process. To accomplish the ordered generation of distinct progenies, NPCs go through multistep transitions of their developmental competence. The molecular mechanisms driving precise temporal coordination of these transitions remains enigmatic. Epigenetic regulation, including changes in chromatin structures, DNA methylation, and histone modifications, has been extensively investigated in the context of cortical neurogenesis. Recent studies of chemical modifications on RNA, termed epitranscriptomics, have also revealed their critical roles in neural development. In this review, we discuss advances in understanding molecular regulation of the sequential lineage specification of NPCs in the embryonic mammalian brain with a focus on epigenetic and epitranscriptomic mechanisms. In particular, the discovery of lineage-specific gene transcripts undergoing rapid turnover in NPCs suggests that NPC developmental fate competence is determined much earlier, before the final cell division, and is more tightly controlled than previously appreciated. We discuss how multiple regulatory systems work in harmony to coordinate NPC behavior and summarize recent findings in the context of a model of epigenetic and transcriptional prepatterning to explain NPC developmental competence.	Animals;Cerebral Cortex;DNA Methylation;Epigenesis, Genetic;Humans;Neural Stem Cells;Time Factors;Transcription, Genetic	Animals;Behavior;Brain;Cell Division;Cerebral Cortex;Chromatin;Competence;Comprehension;DNA Methylation;Epigenesis, Genetic;Epigenetics;Generations;Genes;Histone Code;Humans;Neural Stem Cells;Neurogenesis;Neuroglia;Neurons;RNA;Regulation;Review;Role;Stem Cells;Time Factors;Transcription, Genetic;Work		Yoon, Ki-Jun;Vissers, Caroline;Ming, Guo-Li;Song, Hongjun	[University of Pennsylvania];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine, University of Pennsylvania]	2.00	41	The Journal of cell biology	217	6	1901-1914
U19MH106434	Group 3									10.1038/nprot.2017.152	29470464	2018	Generation of human brain region-specific organoids using a miniaturized spinning bioreactor.	Human brain organoids, 3D self-assembled neural tissues derived from pluripotent stem cells, are important tools for studying human brain development and related disorders. Suspension cultures maintained by spinning bioreactors allow for the growth of large organoids despite the lack of vasculature, but commercially available spinning bioreactors are bulky in size and have low throughput. Here, we describe the procedures for building the miniaturized multiwell spinning bioreactor SpinΩ from 3D-printed parts and commercially available hardware. We also describe how to use SpinΩ to generate forebrain, midbrain and hypothalamus organoids from human induced pluripotent stem cells (hiPSCs). These organoids recapitulate key dynamic features of the developing human brain at the molecular, cellular and structural levels. The reduction in culture volume, increase in throughput and reproducibility achieved using our bioreactor and region-specific differentiation protocols enable quantitative modeling of brain disorders and compound testing. This protocol takes 14-84 d to complete (depending on the type of brain region-specific organoids and desired developmental stages), and organoids can be further maintained over 200 d. Competence with hiPSC culture is required for optimal results.	Bioreactors;Brain;Cell Culture Techniques;Cell Differentiation;Humans;Hydrodynamics;Induced Pluripotent Stem Cells;Organoids;Pluripotent Stem Cells;Printing, Three-Dimensional;Reproducibility of Results	Bioreactors;Brain;Brain Diseases;Cell Culture Techniques;Cell Differentiation;Competence;Culture;Generations;Growth;Human Induced Pluripotent Stem Cells;Humans;Hydrodynamics;Hypothalamus;Induced Pluripotent Stem Cells;Mesencephalon;Organoids;Pluripotent Stem Cells;Printing, Three-Dimensional;Procedures;Prosencephalon;Reproducibility of Results;Self;Suspensions;Tissues		Qian, Xuyu;Jacob, Fadi;Song, Mingxi Max;Nguyen, Ha Nam;Song, Hongjun;Ming, Guo-Li	[Johns Hopkins School of Medicine, Perelman School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine, Perelman School of Medicine, University of Pennsylvania];[Brandeis University];[Johns Hopkins School of Medicine];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania]	10.12	171	Nature protocols	13	3	565-580
U19MH106434	Group 3									10.1186/s13073-017-0512-3	29301565	2018	Modeling psychiatric disorders using patient stem cell-derived neurons: a way forward.	Our understanding of the neurobiology of psychiatric disorders remains limited, and biomarker-based clinical management is yet to be developed. Induced pluripotent stem cell (iPSC) technology has revolutionized our capacity to generate patient-derived neurons to model psychiatric disorders. Here, we highlight advantages and caveats of iPSC disease modeling and outline strategies for addressing current challenges.	Animals;Humans;Induced Pluripotent Stem Cells;Mental Disorders;Models, Biological;Neurons	Animals;Biomarkers;Comprehension;Disease;Humans;Induced Pluripotent Stem Cells;Mental Disorders;Models, Biological;Neurobiology;Neurons;Outline;Patients;Stem Cells;Technology		Vadodaria, Krishna C;Amatya, Debha N;Marchetto, Maria C;Gage, Fred H	[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies]	2.06	38	Genome medicine	10	1	1
U19MH106434	Group 3									10.1038/mp.2016.260	28242870	2018	Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium.	Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein-Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced the hyperexcitability in the lymphoblast-derived LR group but not in the NR group, strengthening the validity and utility of this new human cellular model of BD.	Adult;Antimanic Agents;Antipsychotic Agents;Biomarkers, Pharmacological;Bipolar Disorder;Case-Control Studies;Cell Differentiation;Dentate Gyrus;Female;Hippocampus;Humans;Induced Pluripotent Stem Cells;Lithium;Lithium Compounds;Male;Neurons;Patch-Clamp Techniques	Ability;Adult;Animals;Antimanic Agents;Antipsychotic Agents;B-Lymphocytes;Biomarkers, Pharmacological;Bipolar Disorder;Case-Control Studies;Cell Differentiation;Cells;Classification;Dentate Gyrus;Depression;Female;Fibroblasts;Genetic Heterogeneity;Herpesvirus 4, Human;Hippocampus;Humans;Induced Pluripotent Stem Cells;Life;Lithium;Lithium Compounds;Lymphocytes;Male;Mania;Mental Disorders;Neurons;News;Patch-Clamp Techniques;Patients;Population;Prevalence;Report;Research;Risk;Suicide;Therapeutics		Stern, S;Santos, R;Marchetto, M C;Mendes, A P D;Rouleau, G A;Biesmans, S;Wang, Q-W;Yao, J;Charnay, P;Bang, A G;Alda, M;Gage, F H	[Salk Institute for Biological Studies];[Inserm, Institut de Biologie de l'Ecole Normale Superieure IBENS, National Center for Scientific Research (France), PSL Research University, Salk Institute for Biological Studies, École Normale Supérieure];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[McGill University, Montreal Neurological Institute and Hospital];[Sanford Burnham Prebys Medical Discovery Institute];[Tsinghua University];[Tsinghua University];[Inserm, Institut de Biologie de l'Ecole Normale Superieure IBENS, National Center for Scientific Research (France), PSL Research University, École Normale Supérieure];[Sanford Burnham Prebys Medical Discovery Institute];[Dalhousie University];[Salk Institute for Biological Studies]	4.28	67	Molecular psychiatry	23	6	1453-1465
U19MH106434	Group 3									10.1098/rsob.180031	29794033	2018	Prediction of response to drug therapy in psychiatric disorders.	Personalized medicine has become increasingly relevant to many medical fields, promising more efficient drug therapies and earlier intervention. The development of personalized medicine is coupled with the identification of biomarkers and classification algorithms that help predict the responses of different patients to different drugs. In the last 10 years, the Food and Drug Administration (FDA) has approved several genetically pre-screened drugs labelled as pharmacogenomics in the fields of oncology, pulmonary medicine, gastroenterology, haematology, neurology, rheumatology and even psychiatry. Clinicians have long cautioned that what may appear to be similar patient-reported symptoms may actually arise from different biological causes. With growing populations being diagnosed with different psychiatric conditions, it is critical for scientists and clinicians to develop precision medication tailored to individual conditions. Genome-wide association studies have highlighted the complicated nature of psychiatric disorders such as schizophrenia, bipolar disorder, major depression and autism spectrum disorder. Following these studies, association studies are needed to look for genomic markers of responsiveness to available drugs of individual patients within the population of a specific disorder. In addition to GWAS, the advent of new technologies such as brain imaging, cell reprogramming, sequencing and gene editing has given us the opportunity to look for more biomarkers that characterize a therapeutic response to a drug and to use all these biomarkers for determining treatment options. In this review, we discuss studies that were performed to find biomarkers of responsiveness to different available drugs for four brain disorders: bipolar disorder, schizophrenia, major depression and autism spectrum disorder. We provide recommendations for using an integrated method that will use available techniques for a better prediction of the most suitable drug.	Antipsychotic Agents;Autism Spectrum Disorder;Bipolar Disorder;Clinical Trials as Topic;Depressive Disorder, Major;Genetic Markers;Humans;Mental Disorders;Pharmacogenetics;Pharmacogenomic Variants;Precision Medicine;Schizophrenia	Algorithms;Antipsychotic Agents;Association;Autism Spectrum Disorder;Biomarkers;Biopharmaceuticals;Bipolar Disorder;Brain Diseases;Brain Imaging;Cellular Reprogramming;Classification;Clinical Trials as Topic;Depression;Depressive Disorder, Major;Drug Therapy;Gastroenterology;Gene Editing;Genetic Markers;Genome-Wide Association Study;Genomics;Hematology;Humans;Mental Disorders;Methods;Nature;Neurology;News;Patients;Pharmaceutical Preparations;Pharmacogenetics;Pharmacogenomic Variants;Pharmacogenomics;Population;Precision Medicine;Psychiatry;Pulmonary Medicine;Review;Rheumatology;Schizophrenia;Technology;Therapeutics;United States Food and Drug Administration	autism spectrum disorder;bipolar disorder;classification;major depression;prediction;schizophrenia	Stern, Shani;Linker, Sara;Vadodaria, Krishna C;Marchetto, Maria C;Gage, Fred H	[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies]	1.94	27	Open biology	8	5
U19MH106434	Group 3									10.12688/f1000research.12684.1	29568500	2018	Radial glial cells in the adult dentate gyrus: what are they and where do they come from?	Adult neurogenesis occurs in the dentate gyrus in the mammalian hippocampus. These new neurons arise from neural precursor cells named radial glia-like cells, which are situated in the subgranular zone of the dentate gyrus. Here, we review the emerging topic of precursor heterogeneity in the adult subgranular zone. We also discuss how this heterogeneity may be established during development and focus on the embryonic origin of the dentate gyrus and radial glia-like stem cells. Finally, we discuss recently developed single-cell techniques, which we believe will be critical to comprehensively investigate adult neural stem cell origin and heterogeneity.		Adult;Cells;Dentate Gyrus;Hippocampus;Neural Stem Cells;Neurogenesis;Neurons;News;Radial Glial Cells;Review;Stem Cells	dentate gyrus;radial glial cells;stem cell heterogeneity	Berg, Daniel A;Bond, Allison M;Ming, Guo-Li;Song, Hongjun	[University of Pennsylvania];[University of Pennsylvania];[University of Pennsylvania];[University of Pennsylvania]	2.86	44	F1000Research	7		277
U19MH106434	Group 3									10.1007/s00441-017-2670-4	28812143	2018	Serotonin in psychiatry: in vitro disease modeling using patient-derived neurons.	Several lines of evidence implicate serotonin in the etiology of multiple psychiatric disorders, especially mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD). Much of our current understanding of biological mechanisms underlying serotonergic alterations in mood disorders comes from animal studies. Innovation in induced pluripotent stem cell and transdifferentiation technologies for deriving neurons from adult humans has enabled the study of disease-relevant cellular phenotypes in vitro. In this context, human serotonergic neurons can now be generated using three recently published methodologies. In this mini-review, we broadly discuss evidence linking altered serotonergic neurotransmission in MDD and BD and focus on recently published methods for generating human serotonergic neurons in vitro.	Adult;Animals;Bipolar Disorder;Cell Culture Techniques;Cell Transdifferentiation;Depressive Disorder, Major;Humans;Induced Pluripotent Stem Cells;Mice;Models, Neurological;Serotonergic Neurons;Serotonin;Synaptic Transmission	Adult;Animals;Biopharmaceuticals;Bipolar Disorder;Cell Culture Techniques;Cell Transdifferentiation;Comprehension;Depression;Depressive Disorder, Major;Disease;Humans;In Vitro;Induced Pluripotent Stem Cells;Mental Disorders;Methods;Mice;Models, Neurological;Mood Disorders;Neurons;Patients;Phenotype;Psychiatry;Review;Serotonergic Neurons;Serotonin;Synaptic Transmission;Technology	5-HT;Bipolar;Depression;Human serotonergic neurons;Induced pluripotent stem cells;Mood disorders;Transdifferentiation;iSN	Vadodaria, Krishna C;Stern, Shani;Marchetto, Maria C;Gage, Fred H	[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies]	1.55	21	Cell and tissue research	371	1	161-170
U19MH106434	Group 3									10.1186/s13073-018-0518-5	29386063	2018	Synaptic dysfunction in complex psychiatric disorders: from genetics to mechanisms.	Breakthroughs on many fronts have provided strong evidence to support synaptic dysfunction as a causal factor for neuropsychiatric diseases. Genetic studies have identified variants implicated in novel biological and synaptic pathways, and animal and patient-derived induced pluripotent stem cell-based models have allowed mechanistic investigations of synaptic dysfunction in pathological processes.	Animals;Brain;Humans;Mental Disorders;Synapses	Animals;Biopharmaceuticals;Brain;Genetics;Hereditary Diseases;Humans;Induced Pluripotent Stem Cells;Mental Disorders;Pathologic Processes;Patients;Synapses		Wang, Xinyuan;Christian, Kimberly M;Song, Hongjun;Ming, Guo-Li	[Fudan University, Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania]	0.98	16	Genome medicine	10	1	9
U19MH106434	Group 3									10.1038/d41586-018-04813-x	29691509	2018	The ethics of experimenting with human brain tissue.		Animals;Brain;Chimera;Consciousness;Death;Embryo, Mammalian;Heterografts;Human Experimentation;Humans;In Vitro Techniques;Informed Consent;Mice;Models, Biological;Neurosciences;Organoids;Ownership;Rats;Swine	Animals;Brain;Chimera;Consciousness;Death;Disease;Embryo, Mammalian;Ethics;Heterografts;Human Experimentation;Humans;In Vitro Techniques;Informed Consent;Mice;Models, Biological;Neurosciences;Organoids;Ownership;Rats;Swine;Tissues	Diseases;Neuroscience	Farahany, Nita A;Greely, Henry T;Hyman, Steven;Koch, Christof;Grady, Christine;Pașca, Sergiu P;Sestan, Nenad;Arlotta, Paola;Bernat, James L;Ting, Jonathan;Lunshof, Jeantine E;Iyer, Eswar P R;Hyun, Insoo;Capestany, Beatrice H;Church, George M;Huang, Hao;Song, Hongjun	;;;;;;;;;;;;;;;;	3.73	69	Nature	556	7702	429-432
U19MH106434	Group 3									10.1002/dvdy.24662	30091290	2019	Applications of Human Brain Organoids to Clinical Problems.	Brain organoids are an exciting new technology with the potential to significantly change how diseases of the brain are understood and treated. These three-dimensional neural tissues are derived from the self-organization of pluripotent stem cells, and they recapitulate the developmental process of the human brain, including progenitor zones and rudimentary cortical layers. Brain organoids have been valuable in investigating different aspects of developmental neurobiology and comparative biology. Several characteristics of organoids also make them attractive as models of brain disorders. Data generated from human organoids are more generalizable to patients because of the match in species background. Personalized organoids also can be generated from patient-derived induced pluripotent stem cells. Furthermore, the three-dimensionality of brain organoids supports cellular, mechanical, and topographical cues that are lacking in planar systems. In this review, we discuss the translational potential of brain organoids, using the examples of Zika virus, autism-spectrum disorder, and glioblastoma multiforme to consider how they could contribute to disease modeling, personalized medicine, and testing of therapeutics. We then discuss areas of improvement in organoid technology that will enhance the translational potential of brain organoids, as well as the possibility of their use as substrates for repairing cerebral circuitry after injury. Developmental Dynamics 248:53-64, 2019. © 2018 Wiley Periodicals, Inc.	Animals;Brain;Brain Diseases;Humans;Models, Biological;Organoids;Pluripotent Stem Cells;Translational Research, Biomedical	Animals;Autism Spectrum Disorder;Biology;Brain;Brain Diseases;Cues;Disease;Glioblastoma Multiforme;Humans;Induced Pluripotent Stem Cells;Injuries;Models, Biological;Neurobiology;News;Organizations;Organoids;Patients;Periodical;Pluripotent Stem Cells;Precision Medicine;Review;Self;Technology;Therapeutics;Tissues;Translational Research;Zika Virus	brain structure;cerebral organoid;disease model;personalized medicine;pluripotent stem cells	Chen, H Isaac;Song, Hongjun;Ming, Guo-Li	[Corporal Michael J. Crescenz VAMC, Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania]	4.24	54	Developmental dynamics : an official publication of the American Association of Anatomists	248	1	53-64
U19MH106434	Group 3									10.1242/dev.166074	30992274	2019	Brain organoids: advances, applications and challenges.	Brain organoids are self-assembled three-dimensional aggregates generated from pluripotent stem cells with cell types and cytoarchitectures that resemble the embryonic human brain. As such, they have emerged as novel model systems that can be used to investigate human brain development and disorders. Although brain organoids mimic many key features of early human brain development at molecular, cellular, structural and functional levels, some aspects of brain development, such as the formation of distinct cortical neuronal layers, gyrification, and the establishment of complex neuronal circuitry, are not fully recapitulated. Here, we summarize recent advances in the development of brain organoid methodologies and discuss their applications in disease modeling. In addition, we compare current organoid systems to the embryonic human brain, highlighting features that currently can and cannot be recapitulated, and discuss perspectives for advancing current brain organoid technologies to expand their applications.	Animals;Brain;Humans;Models, Biological;Organoids	Animals;Brain;Cells;Disease;Humans;Models, Biological;Neurosciences;Organoids;Pluripotent Stem Cells;Self;Stem Cells;Technology	Brain organoids;Neuroscience;Stem cell	Qian, Xuyu;Song, Hongjun;Ming, Guo-Li	[Johns Hopkins School of Medicine, University of Pennsylvania];[University of Pennsylvania];[University of Pennsylvania]	14.35	176	Development (Cambridge, England)	146	8
U19MH106434	Group 3									10.1016/j.celrep.2019.06.072	31340148	2019	FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export.	N6-methyladenosine (m6A) modification of mRNA is emerging as a vital mechanism regulating RNA function. Here, we show that fragile X mental retardation protein (FMRP) reads m6A to promote nuclear export of methylated mRNA targets during neural differentiation. Fmr1 knockout (KO) mice show delayed neural progenitor cell cycle progression and extended maintenance of proliferating neural progenitors into postnatal stages, phenocopying methyltransferase Mettl14 conditional KO (cKO) mice that have no m6A modification. RNA-seq and m6A-seq reveal that both Mettl14cKO and Fmr1KO lead to the nuclear retention of m6A-modified FMRP target mRNAs regulating neural differentiation, indicating that both m6A and FMRP are required for the nuclear export of methylated target mRNAs. FMRP preferentially binds m6A-modified RNAs to facilitate their nuclear export through CRM1. The nuclear retention defect can be mitigated by wild-type but not nuclear export-deficient FMRP, establishing a critical role for FMRP in mediating m6A-dependent mRNA nuclear export during neural differentiation.	Active Transport, Cell Nucleus;Adenosine;Animals;Animals, Newborn;Cell Cycle;Cell Differentiation;Cell Proliferation;Cerebral Cortex;Fragile X Mental Retardation Protein;Gene Deletion;Karyopherins;Mice, Knockout;Neural Stem Cells;Neurons;RNA Transport;RNA, Messenger;Receptors, Cytoplasmic and Nuclear	Active Transport, Cell Nucleus;Adenosine;Animals;Animals, Newborn;Cell Cycle;Cell Differentiation;Cell Proliferation;Cerebral Cortex;Fragile X Mental Retardation Protein;Fragile X Syndrome;Gene Deletion;Karyopherins;Lead;Maintenance;Mediating;Methylation;Methyltransferases;Mice;Mice, Knockout;Neural Stem Cells;Neurons;Nuclear Export;RNA;RNA Transport;RNA, Messenger;RNA-Seq;Receptors, Cytoplasmic and Nuclear;Role;Stem Cells	FMRP;Fmr1 knockout;Mettl14;RNA methylation;fragile X syndrome;m(6)A;neural differentiation;neural stem cells;nuclear export;nuclear-cytoplasmic transport	Edens, Brittany M;Vissers, Caroline;Su, Jing;Arumugam, Saravanan;Xu, Zhaofa;Shi, Han;Miller, Nimrod;Rojas Ringeling, Francisca;Ming, Guo-Li;He, Chuan;Song, Hongjun;Ma, Yongchao C	[Feinberg School of Medicine, Lurie Children's Hospital, Northwestern University];[Johns Hopkins School of Medicine];[Feinberg School of Medicine, Lurie Children's Hospital, Northwestern University];[Feinberg School of Medicine, Lurie Children's Hospital, Northwestern University];[Feinberg School of Medicine, Lurie Children's Hospital, Northwestern University];[Feinberg School of Medicine, Lurie Children's Hospital, Northwestern University];[Feinberg School of Medicine, Lurie Children's Hospital, Northwestern University];[Ludwig Maximilians University of Munich];[University of Pennsylvania];[University of Chicago];[University of Pennsylvania];[Feinberg School of Medicine, Lurie Children's Hospital, Northwestern University]	6.05	89	Cell reports	28	4	845-854.e5
U19MH106434	Group 3									10.1039/c8mo00173a	31106784	2019	Kinase network dysregulation in a human induced pluripotent stem cell model of DISC1 schizophrenia.	Protein kinases orchestrate signal transduction pathways involved in central nervous system functions ranging from neurodevelopment to synaptic transmission and plasticity. Abnormalities in kinase-mediated signaling are involved in the pathophysiology of neurological disorders, including neuropsychiatric disorders. Here, we expand on the hypothesis that kinase networks are dysregulated in schizophrenia. We investigated changes in serine/threonine kinase activity in cortical excitatory neurons differentiated from induced pluripotent stem cells (iPSCs) from a schizophrenia patient presenting with a 4 bp mutation in the disrupted in schizophrenia 1 (DISC1) gene and a corresponding control. Using kinome peptide arrays, we demonstrate large scale abnormalities in DISC1 cells, including a global depression of serine/threonine kinase activity, and changes in activity of kinases, including AMP-activated protein kinase (AMPK), extracellular signal-regulated kinases (ERK), and thousand-and-one amino acid (TAO) kinases. Using isogenic cell lines in which the DISC1 mutation is either introduced in the control cell line, or rescued in the schizophrenia cell line, we ascribe most of these changes to a direct effect of the presence of the DISC1 mutation. Investigating the gene expression signatures downstream of the DISC1 kinase network, and mapping them on perturbagen signatures obtained from the Library of Integrated Network-based Cellular Signatures (LINCS) database, allowed us to propose novel drug targets able to reverse the DISC1 kinase dysregulation gene expression signature. Altogether, our findings provide new insight into abnormalities of kinase networks in schizophrenia and suggest possible targets for disease intervention.	Computer Simulation;Humans;Induced Pluripotent Stem Cells;Models, Biological;Mutation;Nerve Tissue Proteins;Neurons;Schizophrenia;Signal Transduction;Synapses;Synaptic Transmission	AMP-Activated Protein Kinases;Amino Acids;Cell Line;Cells;Central Nervous System;Computer Simulation;Database;Depression;Disease;Extracellular Signal-Regulated MAP Kinases;Gene Expression Profiles;Genes;Human Induced Pluripotent Stem Cells;Humans;Induced Pluripotent Stem Cells;Libraries;Models, Biological;Mutation;Nerve Tissue Proteins;Nervous System Diseases;Neurons;News;Patients;Peptides;Pharmaceutical Preparations;Phosphotransferases;Protein Kinases;Protein-Serine-Threonine Kinases;Scales;Schizophrenia;Signal Transduction;Signal Transduction Pathways;Synapses;Synaptic Transmission;TAO		Bentea, Eduard;Depasquale, Erica A K;O'Donovan, Sinead M;Sullivan, Courtney R;Simmons, Micah;Meador-Woodruff, James H;Zhou, Ying;Xu, Chongchong;Bai, Bing;Peng, Junmin;Song, Hongjun;Ming, Guo-Li;Meller, Jarek;Wen, Zhexing;McCullumsmith, Robert E	[Vrije Universiteit Brussel];;;;;;;;;;;;;;	1.34	17	Molecular omics	15	3	173-188
U19MH106434	Group 3	Genomics				GSE113483				10.1038/s41588-019-0472-1	31367015	2019	Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes.	Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform an integrative analysis of chromatin interactions, open chromatin regions and transcriptomes using promoter capture Hi-C, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing, respectively, in four functionally distinct neural cell types: induced pluripotent stem cell (iPSC)-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus-like neurons and primary astrocytes. We identify hundreds of thousands of long-range cis-interactions between promoters and distal promoter-interacting regions, enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several promoter-interacting regions by using clustered regularly interspaced short palindromic repeats (CRISPR) techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP and DRD2 are transcriptionally regulated by physically linked enhancers.	Cell Lineage;Chromatin;Chromosome Mapping;Clustered Regularly Interspaced Short Palindromic Repeats;Enhancer Elements, Genetic;Gene Editing;Gene Expression Regulation;Genetic Markers;Genome, Human;Genome-Wide Association Study;Humans;Induced Pluripotent Stem Cells;Infant;Male;Mental Disorders;Neurons;Polymorphism, Single Nucleotide;Promoter Regions, Genetic	ATAC-Seq;Ability;Address;Astrocytes;Cell Lineage;Cells;Chromatin;Chromosome Mapping;Clustered Regularly Interspaced Short Palindromic Repeats;Dentate Gyrus;Disease;Elements;Enhancer Elements, Genetic;Gene Editing;Gene Expression Regulation;Genes;Genes, Regulator;Genetic Markers;Genetics;Genome, Human;Genome-Wide Association Study;High-Throughput Sequencing;Humans;Induced Pluripotent Stem Cells;Infant;Male;Mental Disorders;Motor Neurons;Mutation;Neurons;Polymorphism, Single Nucleotide;Promoter Regions, Genetic;Risk;Sequence Determinations, RNA;Specificity;Transcriptome;Transposases		Song, Michael;Yang, Xiaoyu;Ren, Xingjie;Maliskova, Lenka;Li, Bingkun;Jones, Ian R;Wang, Chao;Jacob, Fadi;Wu, Kenneth;Traglia, Michela;Tam, Tsz Wai;Jamieson, Kirsty;Lu, Si-Yao;Ming, Guo-Li;Li, Yun;Yao, Jun;Weiss, Lauren A;Dixon, Jesse R;Judge, Luke M;Conklin, Bruce R;Song, Hongjun;Gan, Li;Shen, Yin	[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[Johns Hopkins School of Medicine, Perelman School of Medicine, University of Pennsylvania];[Gladstone Institute of Cardiovascular Disease, University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[Tsinghua University];[Perelman School of Medicine, University of Pennsylvania];[University of North Carolina, Chapel Hill];[Tsinghua University];[University of California, San Francisco];[Salk Institute for Biological Studies];[Gladstone Institute of Cardiovascular Disease, University of California, San Francisco];[Gladstone Institute of Cardiovascular Disease, University of California, San Francisco];[Perelman School of Medicine, University of Pennsylvania];[University of California, San Francisco, Weill Cornell Medicine];[University of California, San Francisco]	2.96	55	Nature genetics	51	8	1252-1262
U19MH106434	Group 3									10.1089/ars.2018.7606	30585734	2019	Mitochondria, Metabolism, and Redox Mechanisms in Psychiatric Disorders.	Significance: Our current knowledge of the pathophysiology and molecular mechanisms causing psychiatric disorders is modest, but genetic susceptibility and environmental factors are central to the etiology of these conditions. Autism, schizophrenia, bipolar disorder and major depressive disorder show genetic gene risk overlap and share symptoms and metabolic comorbidities. The identification of such common features may provide insights into the development of these disorders. Recent Advances: Multiple pieces of evidence suggest that brain energy metabolism, mitochondrial functions and redox balance are impaired to various degrees in psychiatric disorders. Since mitochondrial metabolism and redox signaling can integrate genetic and environmental environmental factors affecting the brain, it is possible that they are implicated in the etiology and progression of psychiatric disorders. Critical Issue: Evidence for direct links between cellular mitochondrial dysfunction and disease features are missing. Future Directions: A better understanding of the mitochondrial biology and its intracellular connections to the nuclear genome, the endoplasmic reticulum and signaling pathways, as well as its role in intercellular communication in the organism, is still needed. This review focuses on the findings that implicate mitochondrial dysfunction, the resultant metabolic changes and oxidative stress as important etiological factors in the context of psychiatric disorders. We also propose a model where specific pathophysiologies of psychiatric disorders depend on circuit-specific impairments of mitochondrial dysfunction and redox signaling at specific developmental stages.	Animals;Humans;Mental Disorders;Mitochondria;Oxidation-Reduction	Animals;Autistic Disorder;Biology;Bipolar Disorder;Brain;Circadian Rhythm;Communication;Comorbidity;Comprehension;Depressive Disorder, Major;Disease;Endoplasmic Reticulum;Energy Metabolism;Future;Genes;Genetic Predisposition to Disease;Genetics;Genome;Humans;Knowledge;Mental Disorders;Metabolism;Mitochondria;Oxidation-Reduction;Oxidative Stress;Review;Risk;Role;Schizophrenia	circadian rhythm;metabolism;mitochondria;oxidative stress;psychiatric disorders;redox signaling	Kim, Yeni;Vadodaria, Krishna C;Lenkei, Zsolt;Kato, Tadafumi;Gage, Fred H;Marchetto, Maria C;Santos, Renata	[National Center for Mental Health (Korea), Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Inserm, Paris Descartes University];[RIKEN Brain Science Institute];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Inserm, Paris Descartes University, Salk Institute for Biological Studies]	6.22	56	Antioxidants & redox signaling	31	4	275-317
U19MH106434	Group 3									10.1016/j.addr.2019.02.007	30797953	2019	Nanoparticle technology and stem cell therapy team up against neurodegenerative disorders.	The convergence of nanoparticles and stem cell therapy holds great promise for the study, diagnosis, and treatment of neurodegenerative disorders. Researchers aim to harness the power of nanoparticles to regulate cellular microenvironment, improve the efficiency of cell and drug delivery to the brain, and enhance the survival of stem cell transplants. Understanding the various properties of different nanoparticles is key to applying them to clinical therapies; the many distinct types of nanoparticles offer unique capacities for medical imaging, diagnosis, and treatment of neurodegeneration disorders. In this review we introduce the biology of Alzheimer's, Parkinson's Disease, and amyotrophic lateral sclerosis, and discuss the potentials and shortcomings of metal, silica, lipid-based, polymeric, and hydrogel nanoparticles for diagnosis and treatment of neurodegenerative disorders. We then provide an overview of current strategies in stem cell therapies and how they can be combined with nanotechnology to improve clinical outcomes.	Animals;Drug Delivery Systems;Humans;Nanostructures;Nanotechnology;Neurodegenerative Diseases;Neuroprotective Agents;Stem Cell Transplantation	Amyotrophic Lateral Sclerosis;Animals;Biology;Brain;Cells;Cellular Microenvironment;Comprehension;Diagnosis;Drug Delivery Systems;Efficiency;Humans;Hydrogels;Lipids;Medical Imaging;Metals;Nanoparticles;Nanostructures;Nanotechnology;Neurodegenerative Diseases;Neuroprotective Agents;Parkinson Disease;Pharmaceutical Preparations;Power, Psychological;Research Personnel;Review;Silicon Dioxide;Stem Cell Transplantation;Stem Cells;Survival;Technology;Therapeutics;Transplants		Vissers, Caroline;Ming, Guo-Li;Song, Hongjun	[Johns Hopkins School of Medicine];[University of Pennsylvania];[University of Pennsylvania]	3.53	33	Advanced drug delivery reviews	148		239-251
U19MH106434	Group 3									10.1186/s12859-019-2723-7	31272389	2019	OSCI: standardized stem cell ontology representation and use cases for stem cell investigation.	Stem cells and stem cell lines are widely used in biomedical research. The Cell Ontology (CL) and Cell Line Ontology (CLO) are two community-based OBO Foundry ontologies in the domains of in vivo cells and in vitro cell line cells, respectively. To support standardized stem cell investigations, we have developed an Ontology for Stem Cell Investigations (OSCI). OSCI imports stem cell and cell line terms from CL and CLO, and investigation-related terms from existing ontologies. A novel focus of OSCI is its application in representing metadata types associated with various stem cell investigations. We also applied OSCI to systematically categorize experimental variables in an induced pluripotent stem cell line cell study related to bipolar disorder. In addition, we used a semi-automated literature mining approach to identify over 200 stem cell gene markers. The relations between these genes and stem cells are modeled and represented in OSCI. OSCI standardizes stem cells found in vivo and in vitro and in various stem cell investigation processes and entities. The presented use cases demonstrate the utility of OSCI in iPSC studies and literature mining related to bipolar disorder.	Animals;Biological Ontologies;Biomedical Research;Humans;Stem Cells	Animals;Biological Ontologies;Biomedical Research;Bipolar Disorder;Cell Line;Cells;Community;Genes;Humans;In Vitro;Induced Pluripotent Stem Cells;Literature;Metadata;Mining;Stem Cells	Bipolar disorder;Cell line ontology;Cell ontology;OSCI;Stem cell;hPSC;iPSC	He, Yongqun;Duncan, William D;Cooper, Daniel J;Hansen, Jens;Iyengar, Ravi;Ong, Edison;Walker, Kendal;Tibi, Omar;Smith, Sam;Serra, Lucas M;Zheng, Jie;Sarntivijai, Sirarat;Schürer, Stephan;O'Shea, K Sue;Diehl, Alexander D	[Michigan Medicine, University of Michigan Medical School];[Roswell Park Comprehensive Cancer Center];[University of Miami];[Icahn School of Medicine];[Icahn School of Medicine];[University of Michigan Medical School];[University of Michigan Medical School];[Johns Hopkins University];;[Jacobs School of Medicine and Biomedical Sciences, University at Buffalo];[University of Pennsylvania];[EMBL-EBI Hinxton];[University of Miami];[University of Michigan Medical School];[Jacobs School of Medicine and Biomedical Sciences, University at Buffalo]	0.26	3	BMC bioinformatics	20	Suppl 5	180
U19MH106434	Group 3	Review								10.1146/annurev-neuro-080317-062231	31283901	2019	Pathophysiology and Mechanisms of Zika Virus Infection in the Nervous System.	In 2015, public awareness of Zika virus (ZIKV) rose in response to alarming statistics of infants with microcephaly being born to women who were infected with the virus during pregnancy, triggering global concern over these potentially devastating consequences. Although we have discovered a great deal about the genome and pathogenesis of this reemergent flavivirus since this recent outbreak, we still have much more to learn, including the nature of the virus-host interactions and mechanisms that determine its tropism and pathogenicity in the nervous system, which are in turn shaped by the continual evolution of the virus. Inevitably, we will find out more about the potential long-term effects of ZIKV exposure on the nervous system from ongoing longitudinal studies. Integrating clinical and epidemiological data with a wider range of animal and human cell culture models will be critical to understanding the pathogenetic mechanisms and developing more specific antiviral compounds and vaccines.	Adult;Animals;Brain;Cells, Cultured;Communicable Diseases, Emerging;Disease Outbreaks;Female;Gene Expression Regulation, Developmental;Gene Expression Regulation, Viral;Genetic Vectors;Host Microbial Interactions;Humans;Infant, Newborn;Macaca mulatta;Mice;Microbiota;Microcephaly;Microglia;Models, Animal;Nervous System Diseases;Neurogenesis;Pregnancy;Pregnancy Complications, Infectious;Receptors, Virus;Twin Studies as Topic;Viral Vaccines;Zika Virus;Zika Virus Infection	Adult;Animals;Antiviral Agents;Awareness;Brain;Cell Culture Techniques;Cells, Cultured;Communicable Diseases, Emerging;Comprehension;Disease Outbreaks;Female;Flavivirus;Gene Expression Regulation, Developmental;Gene Expression Regulation, Viral;Genetic Vectors;Genome;Host Microbial Interactions;Humans;Infant;Infant, Newborn;Longitudinal Studies;Longterm Effects;Macaca mulatta;Mice;Microbiota;Microcephaly;Microglia;Models, Animal;Nature;Nervous System;Nervous System Diseases;Neurogenesis;Pathogenicity;Pregnancy;Pregnancy Complications, Infectious;Receptors, Virus;Rosa;Statistics;Tropism;Twin Studies as Topic;Vaccines;Viral Vaccines;Virus Host Interactions;Viruses;Women;Zika Virus;Zika Virus Infection	Zika;microcephaly;neurodevelopment	Christian, Kimberly M;Song, Hongjun;Ming, Guo-Li	[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania]	1.50	16	Annual review of neuroscience	42		249-269
U19MH106434	Group 3	Patch-seq								10.1016/j.stem.2019.09.002	31585092	2019	Transplantation of Human Brain Organoids: Revisiting the Science and Ethics of Brain Chimeras.	Recent demonstrations of human brain organoid transplantation in rodents have accentuated ethical concerns associated with these entities, especially as they relate to potential "humanization" of host animals. Consideration of established scientific principles can help define the realistic range of expected outcomes in such transplantation studies. This practical approach suggests that augmentation of discrete brain functions in transplant hosts is a more relevant ethical question in the near term than the possibility of "conscious" chimeric animals. We hope that this framework contributes to a balanced approach for proceeding with studies involving brain organoid transplantation and other forms of human-animal brain chimeras.	Animals;Brain;Brain Tissue Transplantation;Chimera;Consciousness;Disease Models, Animal;Ethics, Research;Humans;Mice;Organoids;Practice Guidelines as Topic;Rats;Transplantation, Heterologous	Animals;Brain;Brain Tissue Transplantation;Chimera;Consciousness;Disease Models, Animal;Ethics;Ethics, Research;Form;Hope;Humans;Mice;Organoids;Practice Guidelines as Topic;Rats;Rodentia;Science;Transplantation;Transplantation, Heterologous;Transplants	brain organoid;chimera;consciousness;enhancement;ethics;transplantation	Chen, H Isaac;Wolf, John A;Blue, Rachel;Song, Mingyan Maggie;Moreno, Jonathan D;Ming, Guo-Li;Song, Hongjun	[Corporal Michael J. Crescenz VAMC, Perelman School of Medicine, University of Pennsylvania];[Corporal Michael J. Crescenz VAMC, Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania]	1.60	21	Cell stem cell	25	4	462-472
U19MH106434	Group 3									10.1016/j.biopsych.2020.01.020	32278494	2020	A Physiological Instability Displayed in Hippocampal Neurons Derived From Lithium-Nonresponsive Bipolar Disorder Patients.	We recently reported a hyperexcitability phenotype displayed in dentate gyrus granule neurons derived from patients with bipolar disorder (BD) as well as a hyperexcitability that appeared only in CA3 pyramidal hippocampal neurons that were derived from patients with BD who responded to lithium treatment (lithium responders) and not in CA3 pyramidal hippocampal neurons that were derived from patients with BD who did not respond to lithium (nonresponders). Here we used our measurements of currents in neurons derived from 4 control subjects, 3 patients with BD who were lithium responders, and 3 patients with BD who were nonresponders. We changed the conductances of simulated dentate gyrus and CA3 hippocampal neurons according to our measurements to derive a numerical simulation for BD neurons. The computationally simulated BD dentate gyrus neurons had a hyperexcitability phenotype similar to the experimental results. Only the simulated BD CA3 neurons derived from lithium responder patients were hyperexcitable. Interestingly, our computational model captured a physiological instability intrinsic to hippocampal neurons that were derived from nonresponder patients that we also observed when re-examining our experimental results. This instability was caused by a drastic reduction in the sodium current, accompanied by an increase in the amplitude of several potassium currents. These baseline alterations caused nonresponder BD hippocampal neurons to drastically shift their excitability with small changes to their sodium currents, alternating between hyperexcitable and hypoexcitable states. Our computational model of BD hippocampal neurons that was based on our measurements reproduced the experimental phenotypes of hyperexcitability and physiological instability. We hypothesize that the physiological instability phenotype strongly contributes to affective lability in patients with BD.	Bipolar Disorder;Dentate Gyrus;Hippocampus;Humans;Lithium;Neurons;Pyramidal Cells	Bipolar Disorder;Dentate Gyrus;Hippocampus;Humans;Lithium;Neurons;Patients;Phenotype;Potassium;Pyramidal Cells;Sodium;Therapeutics	Bipolar disorder;CA3 pyramidal;Computational model;Dentate gyrus;Numerical simulation;Physiological instability	Stern, Shani;Sarkar, Anindita;Galor, Dekel;Stern, Tchelet;Mei, Arianna;Stern, Yam;Mendes, Ana P D;Randolph-Moore, Lynne;Rouleau, Guy;Bang, Anne G;Santos, Renata;Alda, Martin;Marchetto, Maria C;Gage, Fred H	[Salk Institute for Biological Studies, University of Haifa];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[McGill University, Montreal Neurological Institute and Hospital];[Sanford Burnham Prebys Medical Discovery Institute];[Inserm, Salk Institute for Biological Studies, University of California];[Dalhousie University];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies]	0.80	6	Biological psychiatry	88	2	150-158
U19MH106434	Group 3					GSE157852				10.1016/j.stem.2020.09.016	33010822	2020	Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism Predominates in Choroid Plexus Epithelium.	Neurological complications are common in patients with COVID-19. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal pathogen of COVID-19, has been detected in some patient brains, its ability to infect brain cells and impact their function is not well understood. Here, we investigated the susceptibility of human induced pluripotent stem cell (hiPSC)-derived monolayer brain cells and region-specific brain organoids to SARS-CoV-2 infection. We found that neurons and astrocytes were sparsely infected, but choroid plexus epithelial cells underwent robust infection. We optimized a protocol to generate choroid plexus organoids from hiPSCs and showed that productive SARS-CoV-2 infection of these organoids is associated with increased cell death and transcriptional dysregulation indicative of an inflammatory response and cellular function deficits. Together, our findings provide evidence for selective SARS-CoV-2 neurotropism and support the use of hiPSC-derived brain organoids as a platform to investigate SARS-CoV-2 infection susceptibility of brain cells, mechanisms of virus-induced brain dysfunction, and treatment strategies.	Animals;Astrocytes;Brain;COVID-19;Cells, Cultured;Choroid Plexus;Gene Expression Regulation;Humans;Neural Stem Cells;Neurons;Organoids;Pluripotent Stem Cells;SARS-CoV-2;Viral Tropism	Ability;Animals;Astrocytes;Brain;COVID-19;Cell Death;Cells;Cells, Cultured;Choroid Plexus;Epithelial Cells;Epithelium;Gene Expression Regulation;Human Induced Pluripotent Stem Cells;Humans;Infections;Mesencephalon;Neural Stem Cells;Neurons;Organoids;Patients;Pluripotent Stem Cells;SARS-CoV-2;Therapeutics;Viral Tropism;Viruses	COVID-19;SARS-CoV-2;astrocyte;brain organoid;choroid plexus organoid;cortical organoid;hippocampal organoid;human iPSCs;hypothalamic organoid;midbrain organoid;neuron;neurotropism	Jacob, Fadi;Pather, Sarshan R;Huang, Wei-Kai;Zhang, Feng;Wong, Samuel Zheng Hao;Zhou, Haowen;Cubitt, Beatrice;Fan, Wenqiang;Chen, Catherine Z;Xu, Miao;Pradhan, Manisha;Zhang, Daniel Y;Zheng, Wei;Bang, Anne G;Song, Hongjun;Carlos de la Torre, Juan;Ming, Guo-Li	[Johns Hopkins School of Medicine, Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine, Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine, Perelman School of Medicine, University of Pennsylvania];[Sanford Burnham Prebys Medical Discovery Institute];[Scripps Research];[Perelman School of Medicine, University of Pennsylvania];[National Center for Advancing Translational Sciences, National Institutes of Health];[National Center for Advancing Translational Sciences, National Institutes of Health];[National Center for Advancing Translational Sciences, National Institutes of Health];[Perelman School of Medicine, University of Pennsylvania];[National Center for Advancing Translational Sciences, National Institutes of Health];[Sanford Burnham Prebys Medical Discovery Institute];[Perelman School of Medicine, University of Pennsylvania];[Scripps Research];[Perelman School of Medicine, University of Pennsylvania]	19.28	143	Cell stem cell	27	6	937-950.e9
U19MH106434	Group 3									10.1016/j.biopsych.2019.09.018	31732108	2020	Mechanisms Underlying the Hyperexcitability of CA3 and Dentate Gyrus Hippocampal Neurons Derived From Patients With Bipolar Disorder.	Approximately 1 in every 50 to 100 people is affected with bipolar disorder (BD), making this disease a major economic burden. The introduction of induced pluripotent stem cell methodology enabled better modeling of this disorder. Having previously studied the phenotype of dentate gyrus granule neurons, we turned our attention to studying the phenotype of CA3 hippocampal pyramidal neurons of 6 patients with BD compared with 4 control individuals. We used patch clamp and quantitative polymerase chain reaction to measure electrophysiological features and RNA expression by specific channel genes. We found that BD CA3 neurons were hyperexcitable only when they were derived from patients who responded to lithium; they featured sustained activity with large current injections and a large, fast after-hyperpolarization, similar to what we previously reported in dentate gyrus neurons. The higher amplitudes and faster kinetics of fast potassium currents correlated with this hyperexcitability. Further supporting the involvement of potassium currents, we observed an overexpression of KCNC1 and KCNC2 in hippocampal neurons derived from lithium responders. Applying specific potassium channel blockers diminished the hyperexcitability. Long-term lithium treatment decreased the hyperexcitability observed in the CA3 neurons derived from lithium responders while increasing sodium currents and reducing fast potassium currents. When differentiating this cohort into spinal motor neurons, we did not observe any changes in the excitability of BD motor neurons compared with control motor neurons. The hyperexcitability of BD neurons is neuronal type specific with the involvement of altered potassium currents that allow for a sustained, continued firing activity.	Bipolar Disorder;Dentate Gyrus;Hippocampus;Humans;Neurons;Patch-Clamp Techniques;Pyramidal Cells;Shaw Potassium Channels	Attention;Bipolar Disorder;Dentate Gyrus;Disease;Economics;Genes;Hippocampus;Humans;Induced Pluripotent Stem Cells;Injections;Kinetics;Lithium;Measures;Motor Neurons;Neurons;Patch-Clamp Techniques;Patients;Persons;Phenotype;Polymerase Chain Reaction;Potassium;Potassium Channel Blockers;Pyramidal Cells;RNA;Shaw Potassium Channels;Sodium;Therapeutics	Bipolar disorder;Dentate gyrus;Hippocampus;Hyperexcitability;Motor neurons;Pyramidal	Stern, Shani;Sarkar, Anindita;Stern, Tchelet;Mei, Arianna;Mendes, Ana P D;Stern, Yam;Goldberg, Gabriela;Galor, Dekel;Nguyen, Thao;Randolph-Moore, Lynne;Kim, Yongsung;Rouleau, Guy;Bang, Anne;Alda, Martin;Santos, Renata;Marchetto, Maria C;Gage, Fred H	[Salk Institute for Biological Studies, University of Haifa];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[McGill University, Montreal Neurological Institute and Hospital];[Sanford Burnham Prebys Medical Discovery Institute];[Dalhousie University];[Salk Institute for Biological Studies, University of Paris];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies]	1.76	13	Biological psychiatry	88	2	139-149
U19MH106434	Group 3									10.1101/cshperspect.a035659	31767646	2020	Modeling Brain Disorders Using Induced Pluripotent Stem Cells.	Brain disorders, from neurodegenerative to psychiatric disorders, are among the most challenging conditions to study because of the intricate nature of the human brain and the limitations of existing model systems in recapitulating all these intricacies. However, innovations in stem cell technologies now allow us to reprogram patient somatic cells to induced pluripotent stem cells (iPSCs), which can then be differentiated to disease-relevant neural and glial cells. iPSCs are a valuable tool to model brain disorders, as they can be derived from patients with known symptom histories, genetics, and drug-response profiles. Here, we discuss the premise and validity of the iPSC-based in vitro model system and highlight key findings from the most commonly studied neurodegenerative and psychiatric disorders.	Animals;Brain;Brain Diseases;Cell Differentiation;Central Nervous System;Chemistry, Pharmaceutical;Drug Design;Genetic Techniques;Humans;Induced Pluripotent Stem Cells;Models, Biological;Models, Neurological;Neurodegenerative Diseases;Neuroglia;Neurons;Pluripotent Stem Cells;Stem Cell Transplantation	Animals;Brain;Brain Diseases;Cell Differentiation;Cells;Central Nervous System;Chemistry, Pharmaceutical;Disease;Drug Design;Genetic Techniques;Genetics;History;Humans;In Vitro;Induced Pluripotent Stem Cells;Mental Disorders;Models, Biological;Models, Neurological;Nature;Neurodegenerative Diseases;Neuroglia;Neurons;Patients;Pharmaceutical Preparations;Pluripotent Stem Cells;Stem Cell Transplantation;Stem Cells;Technology		Vadodaria, Krishna C;Jones, Jeffrey R;Linker, Sara;Gage, Fred H	[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies]	0.47	4	Cold Spring Harbor perspectives in biology	12	6
U19MH106434	Group 3	Review								10.1016/j.biopsych.2019.12.026	32113656	2020	Realizing the Clinical Potential of Computational Psychiatry: Report From the Banbury Center Meeting, February 2019.		Psychiatry	Psychiatry;Report		Browning, Michael;Carter, Cameron S;Chatham, Christopher;Den Ouden, Hanneke;Gillan, Claire M;Baker, Justin T;Chekroud, Adam M;Cools, Roshan;Dayan, Peter;Gold, James;Goldstein, Rita Z;Hartley, Catherine A;Kepecs, Adam;Lawson, Rebecca P;Mourao-Miranda, Janaina;Phillips, Mary L;Pizzagalli, Diego A;Powers, Albert;Rindskopf, David;Roiser, Jonathan P;Schmack, Katharina;Schiller, Daniela;Sebold, Miriam;Stephan, Klaas Enno;Frank, Michael J;Huys, Quentin;Paulus, Martin	[National Health Service, University of Oxford, Warneford Hospital];[University of California, Davis];[Roche Holding AG];[Donders Institute, Radboud University];[Trinity College Dublin];[Harvard Medical School, McLean Hospital];;[Donders Institute, Radboud University, Radboud University Medical Center];[Max Planck Institute for Biological Cybernetics];[University of Maryland, School of Medicine];[Icahn School of Medicine];[New York University];[Cold Spring Harbor Laboratory];[University of Cambridge];[University College London];[University of Pittsburgh];[Harvard Medical School, McLean Hospital];[Yale School of Medicine];[City University of New York];[University College London];[Cold Spring Harbor Laboratory];[Icahn School of Medicine];[Charité - Universitätsmedizin Berlin];[ETH Zurich, Max Planck Institute for Metabolism Research, University College London, University of Zurich, Wellcome Centre for Human Neuroimaging];[Brown University];[ETH Zurich, University College London, University of Zurich];[Laureate Institute for Brain Research]	3.53	20	Biological psychiatry	88	2	e5-e10
U19MH106434	Group 3					GSE137941				10.1016/j.stem.2020.02.002	32142682	2020	Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation.	Human brain organoids provide unique platforms for modeling development and diseases by recapitulating the architecture of the embryonic brain. However, current organoid methods are limited by interior hypoxia and cell death due to insufficient surface diffusion, preventing generation of architecture resembling late developmental stages. Here, we report the sliced neocortical organoid (SNO) system, which bypasses the diffusion limit to prevent cell death over long-term cultures. This method leads to sustained neurogenesis and formation of an expanded cortical plate that establishes distinct upper and deep cortical layers for neurons and astrocytes, resembling the third trimester embryonic human neocortex. Using the SNO system, we further identify a critical role of WNT/β-catenin signaling in regulating human cortical neuron subtype fate specification, which is disrupted by a psychiatric-disorder-associated genetic mutation in patient induced pluripotent stem cell (iPSC)-derived SNOs. These results demonstrate the utility of SNOs for investigating previously inaccessible human-specific, late-stage cortical development and disease-relevant mechanisms.	Humans;Induced Pluripotent Stem Cells;Neocortex;Neurogenesis;Neurons;Organoids	Architecture;Astrocytes;Brain;Cell Death;Cerebral Cortex;Culture;Diffusion;Disease;Generations;Genetics;Humans;Hypoxia;Induced Pluripotent Stem Cells;Lead;Mental Disorders;Methods;Mutation;Neocortex;Neurogenesis;Neurons;Organoids;Patients;Pregnancy Trimester, Third;Prosencephalon;Report;Role;Schizophrenia;beta Catenin	Brain organoid;DISC1;WNT;cerebral cortex;forebrain organoid;human iPSC;lamination;neurodevelopment;neuron fate specification;schizophrenia	Qian, Xuyu;Su, Yijing;Adam, Christopher D;Deutschmann, Andre U;Pather, Sarshan R;Goldberg, Ethan M;Su, Kenong;Li, Shiying;Lu, Lu;Jacob, Fadi;Nguyen, Phuong T T;Huh, Sooyoung;Hoke, Ahmet;Swinford-Jackson, Sarah E;Wen, Zhexing;Gu, Xiaosong;Pierce, R Christopher;Wu, Hao;Briand, Lisa A;Chen, H Isaac;Wolf, John A;Song, Hongjun;Ming, Guo-Li	[Johns Hopkins School of Medicine, University of Pennsylvania];[University of Pennsylvania];[University of Pennsylvania];[Temple University];[University of Pennsylvania];[Children's Hospital of Philadelphia, University of Pennsylvania];[Emory University];[Chinese Ministry of Education, Nantong University, University of Pennsylvania];[University of Pennsylvania];[Johns Hopkins School of Medicine, University of Pennsylvania];[University of Pennsylvania];[University of Pennsylvania];[Johns Hopkins School of Medicine];[University of Pennsylvania];[Emory University School of Medicine];[Chinese Ministry of Education, Nantong University];[University of Pennsylvania];[Emory University, Rollins School of Public Health];[Temple University];[Corporal Michael J. Crescenz VAMC, University of Pennsylvania];[Corporal Michael J. Crescenz VAMC, Emory University, Rollins School of Public Health, University of Pennsylvania];[University of Pennsylvania];[University of Pennsylvania]	10.81	93	Cell stem cell	26	5	766-781.e9
U19MH106434	Group 3									10.1073/pnas.2016416117	33229564	2020	Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity.	Synaptotagmin-7 (Syt7) probably plays an important role in bipolar-like behavioral abnormalities in mice; however, the underlying mechanisms for this have remained elusive. Unlike antidepressants that cause mood overcorrection in bipolar depression, N-methyl-d-aspartate receptor (NMDAR)-targeted drugs show moderate clinical efficacy, for unexplained reasons. Here we identified Syt7 single nucleotide polymorphisms (SNPs) in patients with bipolar disorder and demonstrated that mice lacking Syt7 or expressing the SNPs showed GluN2B-NMDAR dysfunction, leading to antidepressant behavioral consequences and avoidance of overcorrection by NMDAR antagonists. In human induced pluripotent stem cell (iPSC)-derived and mouse hippocampal neurons, Syt7 and GluN2B-NMDARs were localized to the peripheral synaptic region, and Syt7 triggered multiple forms of glutamate release to efficiently activate the juxtaposed GluN2B-NMDARs. Thus, while Syt7 deficiency and SNPs induced GluN2B-NMDAR dysfunction in mice, patient iPSC-derived neurons showed Syt7 deficit-induced GluN2B-NMDAR hypoactivity that was rescued by Syt7 overexpression. Therefore, Syt7 deficits induced mania-like behaviors in mice by attenuating GluN2B activity, which enabled NMDAR antagonists to avoid mood overcorrection.	Adult;Aged;Animals;Behavior, Animal;Bipolar Disorder;Exocytosis;Female;Glutamic Acid;Hippocampus;Humans;Induced Pluripotent Stem Cells;Male;Mania;Mice, Knockout;Middle Aged;Neurons;Receptors, N-Methyl-D-Aspartate;Synaptic Vesicles;Synaptotagmins;Young Adult	Adult;Aged;Animals;Antidepressive Agents;Behavior;Behavior, Animal;Bipolar Disorder;Depression, Bipolar;Exocytosis;Female;Form;Glutamates;Glutamic Acid;Hippocampus;Human Induced Pluripotent Stem Cells;Humans;Induced Pluripotent Stem Cells;Male;Mania;Mental Disorders;Mice;Mice, Knockout;Middle Aged;Mood;Neurons;Patients;Pharmaceutical Preparations;Play;Polymorphism, Single Nucleotide;Receptors, N-Methyl-D-Aspartate;Role;Synaptic Vesicles;Synaptotagmin VII;Synaptotagmins;Treatment Efficacy;Young Adult	bipolar disorder;induced pluripotent stem cell;mania;mental disorder;synaptotagmin 7	Wang, Qiu-Wen;Lu, Si-Yao;Liu, Yao-Nan;Chen, Yun;Wei, Hui;Shen, Wei;Chen, Yan-Fen;Fu, Chong-Lei;Wang, Ying-Han;Dai, Anbang;Huang, Xuan;Gage, Fred H;Xu, Qi;Yao, Jun	[Tsinghua University];[Tsinghua University];[Tsinghua University];[Tsinghua University];[Chinese Academy of Medical Sciences, Institute of Basic Medical Sciences, Beijing, Peking Union Medical College];[Tsinghua University];[Tsinghua University];[Tsinghua University];[Tsinghua University];[Tsinghua University];[Beijing Chao Yang Hospital, Capital Medical University];[Salk Institute for Biological Studies, Tsinghua University];[Chinese Academy of Medical Sciences, Institute of Basic Medical Sciences, Beijing, Peking Union Medical College, Salk Institute for Biological Studies, Tsinghua University];[Salk Institute for Biological Studies, Tsinghua University]	0.90	7	Proceedings of the National Academy of Sciences of the United States of America	117	49	31438-31447
U19MH106434	Group 3									10.1073/pnas.1918165117	32041882	2020	Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice.	The pathogenesis of bipolar disorder (BD) has remained enigmatic, largely because genetic animal models based on identified susceptible genes have often failed to show core symptoms of spontaneous mood cycling. However, pedigree and induced pluripotent stem cell (iPSC)-based analyses have implicated that dysfunction in some key signaling cascades might be crucial for the disease pathogenesis in a subpopulation of BD patients. We hypothesized that the behavioral abnormalities of patients and the comorbid metabolic abnormalities might share some identical molecular mechanism. Hence, we investigated the expression of insulin/synapse dually functioning genes in neurons derived from the iPSCs of BD patients and the behavioral phenotype of mice with these genes silenced in the hippocampus. By these means, we identified synaptotagmin-7 (Syt7) as a candidate risk factor for behavioral abnormalities. We then investigated Syt7 knockout (KO) mice and observed nocturnal manic-like and diurnal depressive-like behavioral fluctuations in a majority of these animals, analogous to the mood cycling symptoms of BD. We treated the Syt7 KO mice with clinical BD drugs including olanzapine and lithium, and found that the drug treatments could efficiently regulate the behavioral abnormalities of the Syt7 KO mice. To further verify whether Syt7 deficits existed in BD patients, we investigated the plasma samples of 20 BD patients and found that the Syt7 mRNA level was significantly attenuated in the patient plasma compared to the healthy controls. We therefore concluded that Syt7 is likely a key factor for the bipolar-like behavioral abnormalities.	Adult;Animals;Behavior;Bipolar Disorder;Female;Humans;Induced Pluripotent Stem Cells;Male;Mice;Mice, Knockout;Neurons;Synaptotagmins;Young Adult	Adult;Animals;Behavior;Bipolar Disorder;Disease;Female;Genes;Genetics;Hippocampus;Humans;Induced Pluripotent Stem Cells;Insulin;Lithium;Male;Mental Disorders;Mice;Mice, Knockout;Models, Animal;Mood;Neurons;Olanzapine;Patients;Pedigree;Pharmaceutical Preparations;Phenotype;Plasma;RNA, Messenger;Risk Factors;Synapses;Synaptotagmin VII;Synaptotagmins;Therapeutics;Young Adult	bipolar disorder;induced pluripotent stem cell;mental disorder;synaptotagmin-7	Shen, Wei;Wang, Qiu-Wen;Liu, Yao-Nan;Marchetto, Maria C;Linker, Sara;Lu, Si-Yao;Chen, Yun;Liu, Chuihong;Guo, Chongye;Xing, Zhikai;Shi, Wei;Kelsoe, John R;Alda, Martin;Wang, Hongwei;Zhong, Yi;Sui, Sen-Fang;Zhao, Mei;Yang, Yiming;Mi, Shuangli;Cao, Liping;Gage, Fred H;Yao, Jun	[Tsinghua University];[Tsinghua University];[Tsinghua University];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Tsinghua University];[Tsinghua University];[Guangzhou Medical University];[Beijing Institute of Genomics Chinese Academy of Sciences, University of Chinese Academy of Sciences];[Beijing Institute of Genomics Chinese Academy of Sciences, University of Chinese Academy of Sciences];[Beihang University];[University of California, San Diego];[Dalhousie University];[Tsinghua University];[Tsinghua University];[Tsinghua University];[Chinese Academy of Sciences, University of Chinese Academy of Sciences];[Jiangsu Normal University];[Beijing Institute of Genomics Chinese Academy of Sciences, University of Chinese Academy of Sciences];[Guangzhou Medical University];[Salk Institute for Biological Studies, Tsinghua University];[Salk Institute for Biological Studies, Tsinghua University]	0.85	7	Proceedings of the National Academy of Sciences of the United States of America	117	8	4392-4399
U19MH106434	Group 3									10.1016/j.stemcr.2021.02.004	33667413	2021	Altered Neuronal Support and Inflammatory Response in Bipolar Disorder Patient-Derived Astrocytes.	Bipolar disorder (BD) is characterized by cyclical mood shifts. Studies indicate that BD patients have a peripheral pro-inflammatory state and alterations in glial populations in the brain. We utilized an in vitro model to study inflammation-related phenotypes of astrocytes derived from induced pluripotent stem cells (iPSCs) generated from BD patients and healthy controls. BD astrocytes showed changes in transcriptome and induced a reduction in neuronal activity when co-cultured with neurons. IL-1β-stimulated BD astrocytes displayed a unique inflammatory gene expression signature and increased secretion of IL-6. Conditioned medium from stimulated BD astrocytes reduced neuronal activity, and this effect was partially blocked by IL-6 inactivating antibody. Our results suggest that BD astrocytes are functionally less supportive of neuronal excitability and this effect is partially mediated by IL-6. We confirmed higher IL-6 in blood in a distinct cohort of BD patients, highlighting the potential role of astrocyte-mediated inflammatory signaling in BD neuropathology.	Astrocytes;Bipolar Disorder;Coculture Techniques;Humans;Induced Pluripotent Stem Cells;Inflammation;Interleukin-1beta;Interleukin-6;Neuroglia;Neurons	Antibodies;Astrocytes;Bipolar Disorder;Blood;Bodily Secretions;Brain;Coculture Techniques;Culture Media, Conditioned;Cytokines;Gene Expression Profiles;Humans;In Vitro;Induced Pluripotent Stem Cells;Inflammation;Interleukin-1beta;Interleukin-6;Mood;Mood Disorders;Neuroglia;Neurons;Neuropathology;Patients;Phenotype;Population;Psychiatry;Role;Transcriptome	IL-6;astrocytes;cytokine;glia;iPSC;inflammation;mood disorders;neuronal activity;psychiatry	Vadodaria, Krishna C;Mendes, Ana P D;Mei, Arianna;Racha, Vipula;Erikson, Galina;Shokhirev, Maxim N;Oefner, Ruth;Heard, Kelly J;McCarthy, Michael J;Eyler, Lisa;Kelsoe, John R;Santos, Renata;Marchetto, Maria C;Gage, Fred H	[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Inserm, Salk Institute for Biological Studies, University of Paris];[Salk Institute for Biological Studies, University of California, San Diego];[Salk Institute for Biological Studies]	1.33	5	Stem cell reports	16	4	825-835
U19MH106434	Group 3	Review								10.1016/bs.ctdb.2020.12.011	33706925	2021	Building the brain from scratch: Engineering region-specific brain organoids from human stem cells to study neural development and disease.	Human brain development is an intricate process that involves precisely timed coordination of cell proliferation, fate specification, neuronal differentiation, migration, and integration of diverse cell types. Understanding of these fundamental processes, however, has been largely constrained by limited access to fetal brain tissue and the inability to prospectively study neurodevelopment in humans at the molecular, cellular and system levels. Although non-human model organisms have provided important insights into mechanisms underlying brain development, these systems do not fully recapitulate many human-specific features that often relate to disease. To address these challenges, human brain organoids, self-assembled three-dimensional neural aggregates, have been engineered from human pluripotent stem cells to model the architecture and cellular diversity of the developing human brain. Recent advancements in neural induction and regional patterning using small molecules and growth factors have yielded protocols for generating brain organoids that recapitulate the structure and neuronal composition of distinct brain regions. Here, we first provide an overview of early mammalian brain development with an emphasis on molecular cues that guide region specification. We then focus on recent efforts in generating human brain organoids that model the development of specific brain regions and highlight endeavors to enhance the cellular complexity to better mimic the in vivo developing human brain. We also provide examples of how organoid models have enhanced our understanding of human neurological diseases and conclude by discussing limitations of brain organoids with our perspectives on future advancements to maximize their potential.	Brain;Humans;Organoids;Stem Cells	Address;Architecture;Brain;Brain Diseases;Cell Proliferation;Cells;Comprehension;Cues;Disease;Engineering;Future;Growth Factors;Humans;Organoids;Pluripotent Stem Cells;Self;Stem Cells;Tissues	Brain organoids;Developmental brain disorders;Neural development;Patterning;Pluripotent stem cells	Jacob, Fadi;Schnoll, Jordan G;Song, Hongjun;Ming, Guo-Li	[Johns Hopkins School of Medicine, Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania]		3	Current topics in developmental biology	142		477-530
U19MH106434	Group 3	Genomics				GSE166939				10.1016/j.biopsych.2021.04.023	34247782	2021	CYFIP1 Dosages Exhibit Divergent Behavioral Impact via Diametric Regulation of NMDA Receptor Complex Translation in Mouse Models of Psychiatric Disorders.	Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear. We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo. Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities. CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.		Autism Spectrum Disorder;Behavior;Brain Diseases;Classification;Exhibition;Gene Dosage;Genes;Immunoprecipitation;Mental Disorders;Mice;Phenotype;Protein Biosynthesis;RNA;RNA, Messenger;RNA-Binding Proteins;Receptors, N-Methyl-D-Aspartate;Regulation;Schizophrenia;Synapses;Translations	Autism spectrum disorder;Gene dosage;NMDA receptor;RNA binding protein;Schizophrenia;Synaptic protein translation	Kim, Nam-Shik;Ringeling, Francisca Rojas;Zhou, Ying;Nguyen, Ha Nam;Temme, Stephanie J;Lin, Yu-Ting;Eacker, Stephen;Dawson, Valina L;Dawson, Ted M;Xiao, Bo;Hsu, Kuei-Sen;Canzar, Stefan;Li, Weidong;Worley, Paul;Christian, Kimberly M;Yoon, Ki-Jun;Song, Hongjun;Ming, Guo-Li	[University of Pennsylvania];[Johns Hopkins School of Medicine, Ludwig Maximilians University of Munich];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[University of Pennsylvania];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[National Cheng Kung University];[Ludwig Maximilians University of Munich];[Shanghai Jiao Tong University];[Johns Hopkins School of Medicine];[University of Pennsylvania];[University of Pennsylvania];[University of Pennsylvania];[University of Pennsylvania]		0	Biological psychiatry
U19MH106434	Group 3					GSE159487				10.1038/s41380-020-00981-3	33398088	2021	Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients.	Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/β-catenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1, and reduced excitability in NR neurons. In addition, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.	Bipolar Disorder;Glycogen Synthase Kinase 3 beta;Humans;Lithium;Lymphoid Enhancer-Binding Factor 1;Neurons;Wnt Signaling Pathway;beta Catenin	Affect;Bipolar Disorder;Dentate Gyrus;Down-Regulation;Form;Genes;Glycogen Synthase Kinase 3 beta;Humans;Induced Pluripotent Stem Cells;Lithium;Lymphoid Enhancer-Binding Factor 1;Manic Episode;Mood;Neurons;News;Patients;Pharmaceutical Preparations;Population;Program;Therapeutics;Valproic Acid;Wnt Signaling Pathway;Wnt beta-Catenin Signaling Pathway;beta Catenin		Santos, Renata;Linker, Sara B;Stern, Shani;Mendes, Ana P D;Shokhirev, Maxim N;Erikson, Galina;Randolph-Moore, Lynne;Racha, Vipula;Kim, Yeni;Kelsoe, John R;Bang, Anne G;Alda, M;Marchetto, Maria C;Gage, Fred H	[Inserm, Salk Institute for Biological Studies, University of Paris];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies, University of Haifa];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Salk Institute for Biological Studies];[Dongguk University, Salk Institute for Biological Studies];[University of California, San Diego];[Sanford Burnham Prebys Medical Discovery Institute];[Dalhousie University];[Salk Institute for Biological Studies, University of California, San Diego];[Salk Institute for Biological Studies]	3.44	11	Molecular psychiatry	26	6	2440-2456
U19MH106434	Group 3									10.1038/s41380-020-00862-9	32839513	2021	Inositol monophosphatase 1 (IMPA1) mutation in intellectual disability patients impairs neurogenesis but not gliogenesis.	A homozygous mutation in the inositol monophosphatase 1 (IMPA1) gene was recently identified in nine individuals with severe intellectual disability (ID) and disruptive behavior. These individuals belong to the same family from Northeastern Brazil, which has 28 consanguineous marriages and 59 genotyped family members. IMPA1 is responsible for the generation of free inositol from de novo biosynthesis and recycling from inositol polyphosphates and participates in the phosphatidylinositol signaling pathway. To understand the role of IMPA1 deficiency in ID, we generated induced pluripotent stem cells (iPSCs) from patients and neurotypical controls and differentiated these into hippocampal dentate gyrus-like neurons and astrocytes. IMPA1-deficient neuronal progenitor cells (NPCs) revealed substantial deficits in proliferation and neurogenic potential. At low passage NPCs (P1 to P3), we observed cell cycle arrest, apoptosis, progressive change to a glial morphology and reduction in neuronal differentiation. These observations were validated by rescuing the phenotype with myo-inositol supplemented media during differentiation of patient-derived iPSCs into neurons and by the reduction of neurogenic potential in control NPCs-expressing shIMPA1. Transcriptome analysis showed that NPCs and neurons derived from ID patients have extensive deregulation of gene expression affecting pathways necessary for neurogenesis and upregulation of gliogenic genes. IMPA1 deficiency did not affect cell cycle progression or survival in iPSCs and glial progenitor cells or astrocyte differentiation. Therefore, this study shows that the IMPA1 mutation specifically affects NPC survival and neuronal differentiation.	Cell Differentiation;Humans;Intellectual Disability;Mutation;Neurogenesis;Phosphoric Monoester Hydrolases	Affect;Apoptosis;Astrocytes;Brazil;Cell Cycle;Cell Cycle Arrest;Cell Differentiation;Consanguineous Marriage;Dentate Gyrus;Disruptive Behavior;Family;Family Members;Gene Expression;Gene Expression Profiling;Generations;Genes;Humans;Id;Induced Pluripotent Stem Cells;Inositol;Intellectual Disability;Mutation;Neurogenesis;Neurons;Observation;Patients;Phenotype;Phosphatidylinositols;Phosphoric Monoester Hydrolases;Polyphosphates;Recycling;Role;Stem Cells;Survival;Up-Regulation		Figueiredo, Thalita;Mendes, Ana P D;Moreira, Danielle P;Goulart, Ernesto;Oliveira, Danyllo;Kobayashi, Gerson S;Stern, Shani;Kok, Fernando;Marchetto, Maria C;Santos, Renata;Gage, Fred H;Zatz, Mayana	[Federal University of Alagoas, Salk Institute for Biological Studies, University of São Paulo];[Salk Institute for Biological Studies];[University of São Paulo];[University of São Paulo];[University of São Paulo];[University of São Paulo];[Salk Institute for Biological Studies, University of Haifa];[University of São Paulo];[Salk Institute for Biological Studies];[Inserm, Salk Institute for Biological Studies, University of Paris];[Salk Institute for Biological Studies];[University of São Paulo]		1	Molecular psychiatry	26	7	3558-3571
U19MH106434	Group 3	Review								10.1016/j.semcdb.2020.05.026	32561297	2021	Modeling neurological disorders using brain organoids.	Neurological disorders are challenging to study given the complexity and species-specific features of the organ system. Brain organoids are three dimensional structured aggregates of neural tissue that are generated by self-organization and differentiation from pluripotent stem cells under optimized culture conditions. These brain organoids exhibit similar features of structural organization and cell type diversity as the developing human brain, creating opportunities to recapitulate disease phenotypes that are not otherwise accessible. Here we review the initial attempt in the field to apply brain organoid models for the study of many different types of human neurological disorders across a wide range of etiologies and pathophysiologies. Forthcoming advancements in both brain organoid technology as well as analytical methods have significant potentials to advance the understanding of neurological disorders and to uncover opportunities for meaningful therapeutic intervention.	Brain;Cell Differentiation;Ependymoglial Cells;Gene Expression Regulation;Humans;Models, Biological;Mutation;Neoplasms;Nerve Tissue Proteins;Nervous System Diseases;Neurodegenerative Diseases;Neurons;Organoids;Pluripotent Stem Cells;Primary Cell Culture;Virus Diseases	Brain;Cell Differentiation;Cells;Comprehension;Culture;Disease;Ependymoglial Cells;Exhibition;Gene Expression Regulation;Humans;Methods;Models, Biological;Mutation;Neoplasms;Nerve Tissue Proteins;Nervous System Diseases;Neurodegenerative Diseases;Neurons;Organizations;Organoids;Phenotype;Pluripotent Stem Cells;Primary Cell Culture;Review;Self;Stem Cells;Technology;Therapeutics;Tissues;Virus Diseases	3D culture;Brain organoid;Disease modeling;Neurological disease;Stem cell	Zhang, Daniel Y;Song, Hongjun;Ming, Guo-Li	[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania];[Perelman School of Medicine, University of Pennsylvania]	1.47	5	Seminars in cell & developmental biology	111		4-14
U19MH106434	Group 3	Genomics, Electrophysiology								10.1038/s41467-021-21713-3	33658519	2021	Pharmacological rescue in patient iPSC and mouse models with a rare DISC1 mutation.	We previously identified a causal link between a rare patient mutation in DISC1 (disrupted-in-schizophrenia 1) and synaptic deficits in cortical neurons differentiated from isogenic patient-derived induced pluripotent stem cells (iPSCs). Here we find that transcripts related to phosphodiesterase 4 (PDE4) signaling are significantly elevated in human cortical neurons differentiated from iPSCs with the DISC1 mutation and that inhibition of PDE4 or activation of the cAMP signaling pathway functionally rescues synaptic deficits. We further generated a knock-in mouse line harboring the same patient mutation in the Disc1 gene. Heterozygous Disc1 mutant mice exhibit elevated levels of PDE4s and synaptic abnormalities in the brain, and social and cognitive behavioral deficits. Pharmacological inhibition of the PDE4 signaling pathway rescues these synaptic, social and cognitive behavioral abnormalities. Our study shows that patient-derived isogenic iPSC and humanized mouse disease models are integral and complementary for translational studies with a better understanding of underlying molecular mechanisms.	Animals;Behavior, Animal;Cerebral Cortex;Cyclic Nucleotide Phosphodiesterases, Type 4;Disease Models, Animal;Female;Gene Expression;Humans;Induced Pluripotent Stem Cells;Male;Mice, Mutant Strains;Mutation;Nerve Tissue Proteins;Neurons;Phosphodiesterase 4 Inhibitors;Rolipram;Schizophrenia;Synapses	Adenosine Monophosphate;Animals;Behavior, Animal;Brain;Cerebral Cortex;Comprehension;Cyclic Nucleotide Phosphodiesterases, Type 4;Disease;Disease Models, Animal;Exhibition;Female;Gene Expression;Genes;Humans;Induced Pluripotent Stem Cells;Male;Mice;Mice, Mutant Strains;Mutation;Nerve Tissue Proteins;Neurons;Patients;Phosphodiesterase 4 Inhibitors;Rolipram;Schizophrenia;Synapses		Kim, Nam-Shik;Wen, Zhexing;Liu, Jing;Zhou, Ying;Guo, Ziyuan;Xu, Chongchong;Lin, Yu-Ting;Yoon, Ki-Jun;Park, Junhyun;Cho, Michelle;Kim, Minji;Wang, Xinyuan;Yu, Huimei;Sakamuru, Srilatha;Christian, Kimberly M;Hsu, Kuei-Sen;Xia, Menghang;Li, Weidong;Ross, Christopher A;Margolis, Russell L;Lu, Xin-Yun;Song, Hongjun;Ming, Guo-Li	[Korea Institute of Science and Technology, University of Pennsylvania];[Emory University School of Medicine];[University of Texas Health Science Center at San Antonio];[Johns Hopkins School of Medicine, Shanghai Jiao Tong University];[University of Pennsylvania];[Emory University School of Medicine];[Johns Hopkins School of Medicine, National Cheng Kung University];[Korea Institute of Science and Technology, University of Pennsylvania];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[University of Pennsylvania];[Johns Hopkins School of Medicine];[National Center for Advancing Translational Sciences, National Institutes of Health];[University of Pennsylvania];[National Cheng Kung University];[National Center for Advancing Translational Sciences, National Institutes of Health];[Shanghai Jiao Tong University];[Johns Hopkins School of Medicine];[Johns Hopkins School of Medicine];[Augusta University, University of Texas Health Science Center at San Antonio];[University of Pennsylvania];[University of Pennsylvania]		3	Nature communications	12	1	1398
U19MH106434	Group 3									10.1038/s41380-019-0485-2	31444471	2021	Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.	Psychiatric disorders are a collection of heterogeneous mental disorders arising from a contribution of genetic and environmental insults, many of which molecularly converge on transcriptional dysregulation, resulting in altered synaptic functions. The underlying mechanisms linking the genetic lesion and functional phenotypes remain largely unknown. Patient iPSC-derived neurons with a rare frameshift DISC1 (Disrupted-in-schizophrenia 1) mutation have previously been shown to exhibit aberrant gene expression and deficits in synaptic functions. How DISC1 regulates gene expression is largely unknown. Here we show that Activating Transcription Factor 4 (ATF4), a DISC1 binding partner, is more abundant in the nucleus of DISC1 mutant human neurons and exhibits enhanced binding to a collection of dysregulated genes. Functionally, overexpressing ATF4 in control neurons recapitulates deficits seen in DISC1 mutant neurons, whereas transcriptional and synaptic deficits are rescued in DISC1 mutant neurons with CRISPR-mediated heterozygous ATF4 knockout. By solving the high-resolution atomic structure of the DISC1-ATF4 complex, we show that mechanistically, the mutation of DISC1 disrupts normal DISC1-ATF4 interaction, and results in excessive ATF4 binding to DNA targets and deregulated gene expression. Together, our study identifies the molecular and structural basis of an DISC1-ATF4 interaction underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.	Activating Transcription Factor 4;Humans;Induced Pluripotent Stem Cells;Mental Disorders;Nerve Tissue Proteins;Neurons	Activating Transcription Factor 4;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;DNA;Exhibition;Gene Expression;Genes;Genetics;Humans;Induced Pluripotent Stem Cells;Mental Disorders;Mutation;Nerve Tissue Proteins;Neurons;Patients;Phenotype;Schizophrenia		Wang, Xinyuan;Ye, Fei;Wen, Zhexing;Guo, Ziyuan;Yu, Chuan;Huang, Wei-Kai;Rojas Ringeling, Francisca;Su, Yijing;Zheng, Wei;Zhou, Guomin;Christian, Kimberly M;Song, Hongjun;Zhang, Mingjie;Ming, Guo-Li	[Fudan University, University of Pennsylvania];[Hong Kong University of Science and Technology];[Emory University School of Medicine];[University of Pennsylvania];[Hong Kong University of Science and Technology];[Johns Hopkins School of Medicine, University of Pennsylvania];[Johns Hopkins School of Medicine];[University of Pennsylvania];[National Center for Advancing Translational Sciences, National Institutes of Health];[Fudan University];[University of Pennsylvania];[University of Pennsylvania];[Hong Kong University of Science and Technology];[University of Pennsylvania]	3.96	14	Molecular psychiatry	26	4	1346-1360
U01MH115727	Group 4	Review								10.1016/j.neuron.2011.05.003	21609821	2011	Constructing and deconstructing stem cell models of neurological disease.	Among the disciplines of medicine, the study of neurological disorders is particularly challenging. The fundamental inaccessibility of the human neural types affected by disease prevents their isolation for in vitro studies of degenerative mechanisms or for drug screening efforts. However, the ability to reprogram readily accessible tissue from patients into pluripotent stem (iPS) cells may now provide a general solution to this shortage of human neurons. Gradually improving methods for directing the differentiation of patient-specific stem cells has enabled the production of several neural cell types affected by disease. Furthermore, initial studies with stem cell lines derived from individuals with pediatric, monogenic disorders have validated the stem cell approach to disease modeling, allowing relevant neural phenotypes to be observed and studied. Whether iPS cell-derived neurons will always faithfully recapitulate the same degenerative processes observed in patients and serve as platforms for drug discovery relevant to common late-onset diseases remains to be determined.	Animals;Cell Differentiation;Humans;Models, Theoretical;Nervous System Diseases;Pluripotent Stem Cells;Stem Cell Transplantation;Stem Cells	Ability;Animals;Cell Differentiation;Cells;Disease;Drug Discovery;Drug Evaluation, Preclinical;Humans;In Vitro;Late Onset Disorders;Medicine;Methods;Microscopy, Electron, Scanning Transmission;Models, Theoretical;Nervous System Diseases;Neurons;Patients;Pediatrics;Phenotype;Pluripotent Stem Cells;Production;Solutions;Stem Cell Transplantation;Stem Cells;Tissues		Han, Steve S W;Williams, Luis A;Eggan, Kevin C	[Massachusetts General Hospital];;	2.63	109	Neuron	70	4	626-44
U01MH115727	Group 4					GSE112732				10.1016/j.celrep.2018.04.066	29791859	2018	Combining NGN2 Programming with Developmental Patterning Generates Human Excitatory Neurons with NMDAR-Mediated Synaptic Transmission.	Transcription factor programming of pluripotent stem cells (PSCs) has emerged as an approach to generate human neurons for disease modeling. However, programming schemes produce a variety of cell types, and those neurons that are made often retain an immature phenotype, which limits their utility in modeling neuronal processes, including synaptic transmission. We report that combining NGN2 programming with SMAD and WNT inhibition generates human patterned induced neurons (hpiNs). Single-cell analyses showed that hpiN cultures contained cells along a developmental continuum, ranging from poorly differentiated neuronal progenitors to well-differentiated, excitatory glutamatergic neurons. The most differentiated neurons could be identified using a CAMK2A::GFP reporter gene and exhibited greater functionality, including NMDAR-mediated synaptic transmission. We conclude that utilizing single-cell and reporter gene approaches for selecting successfully programmed cells for study will greatly enhance the utility of hpiNs and other programmed neuronal populations in the modeling of nervous system disorders.	Adult;Basic Helix-Loop-Helix Transcription Factors;Body Patterning;Calcium-Calmodulin-Dependent Protein Kinase Type 2;Cell Differentiation;Cells, Cultured;Fetus;Gene Expression Regulation;Humans;Nerve Tissue Proteins;Neurons;Pluripotent Stem Cells;Receptors, AMPA;Receptors, Glutamate;Receptors, N-Methyl-D-Aspartate;Smad Proteins;Synapses;Synaptic Transmission;Time Factors;Transcription, Genetic;Wnt Proteins	Adult;Basic Helix-Loop-Helix Transcription Factors;Body Patterning;Calcium-Calmodulin-Dependent Protein Kinase Type 2;Cell Differentiation;Cells;Cells, Cultured;Culture;Disease;Fetus;Gene Expression Regulation;Genes, Reporter;Humans;Nerve Tissue Proteins;Nervous System Diseases;Neurons;Phenotype;Pluripotent Stem Cells;Population;Receptors, AMPA;Receptors, Glutamate;Receptors, N-Methyl-D-Aspartate;Report;Single-Cell Analysis;Smad Proteins;Stem Cells;Synapses;Synaptic Transmission;Time Factors;Transcription Factors;Transcription, Genetic;Wnt Proteins	AMPAR;CAMK2A;NGN2;NMDAR;Wnt inhibition;dual SMAD inhibition;excitatory neurons;human stem cell;neuronal differentiation;single cell profiling	Nehme, Ralda;Zuccaro, Emanuela;Ghosh, Sulagna Dia;Li, Chenchen;Sherwood, John L;Pietilainen, Olli;Barrett, Lindy E;Limone, Francesco;Worringer, Kathleen A;Kommineni, Sravya;Zang, Ying;Cacchiarelli, Davide;Meissner, Alex;Adolfsson, Rolf;Haggarty, Stephen;Madison, Jon;Muller, Matthias;Arlotta, Paola;Fu, Zhanyan;Feng, Guoping;Eggan, Kevin	[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Novartis AG];[Novartis AG];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University];[Harvard University];[Umeå University];[Massachusetts General Hospital];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Novartis AG];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University, Stanley Center for Psychiatric Research at Broad Institute]	4.38	80	Cell reports	23	8	2509-2523
U01MH115727	Group 4									10.1038/s41593-019-0530-0	31768050	2019	Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein.	To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes including SOD1, NEK1 and FUS. We also observed multiple distinct protein-truncating variants in a highly constrained gene, DNAJC7. The signal in DNAJC7 exceeded genome-wide significance, and immunoblotting assays showed depletion of DNAJC7 protein in fibroblasts in a patient with ALS carrying the p.Arg156Ter variant. DNAJC7 encodes a member of the heat-shock protein family, HSP40, which, along with HSP70 proteins, facilitates protein homeostasis, including folding of newly synthesized polypeptides and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of aberrant proteins can occur and lead to protein aggregation, which is a pathological hallmark of neurodegeneration. Our results highlight DNAJC7 as a novel gene for ALS.	Amyotrophic Lateral Sclerosis;Case-Control Studies;Exome;Female;Genetic Predisposition to Disease;Genetic Variation;Heat-Shock Proteins;Humans;Male;Molecular Chaperones	Amyotrophic Lateral Sclerosis;Carrying;Case-Control Studies;Exome;Family;Female;Fibroblasts;Genes;Genetic Predisposition to Disease;Genetic Variation;Genome;Heat-Shock Proteins;Humans;Immunoblotting;Lead;Male;Molecular Chaperones;Patients;Polypeptides;Proteins;Proteostasis		Farhan, Sali M K;Howrigan, Daniel P;Abbott, Liam E;Klim, Joseph R;Topp, Simon D;Byrnes, Andrea E;Churchhouse, Claire;Phatnani, Hemali;Smith, Bradley N;Rampersaud, Evadnie;Wu, Gang;Wuu, Joanne;Shatunov, Aleksey;Iacoangeli, Alfredo;Al Khleifat, Ahmad;Mordes, Daniel A;Ghosh, Sulagna;;;;;Eggan, Kevin;Rademakers, Rosa;McCauley, Jacob L;Schüle, Rebecca;Züchner, Stephan;Benatar, Michael;Taylor, J Paul;Nalls, Michael;Gotkine, Marc;Shaw, Pamela J;Morrison, Karen E;Al-Chalabi, Ammar;Traynor, Bryan;Shaw, Christopher E;Goldstein, David B;Harms, Matthew B;Daly, Mark J;Neale, Benjamin M	[Broad Institute of MIT and Harvard, Harvard Medical School, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research at Broad Institute];[Harvard Medical School, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research at Broad Institute];[Harvard Medical School, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research at Broad Institute];[Harvard Stem Cell Institute, Harvard University];[Institute of Psychiatry, Psychology and Neuroscience, King's College London];[Harvard Medical School, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research at Broad Institute];[Harvard Medical School, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research at Broad Institute];[New York Genome Center];[Institute of Psychiatry, Psychology and Neuroscience, King's College London];[St. Jude Children's Research Hospital];[St. Jude Children's Research Hospital];[University of Miami];[King's College London];[Institute of Psychiatry, Psychology and Neuroscience, King's College London];[King's College London];[Harvard Stem Cell Institute, Harvard University];[Harvard Stem Cell Institute, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];;;;;[Harvard Stem Cell Institute, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Mayo Clinic, Jacksonville];[Miller School of Medicine];[German Center for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen];[Miller School of Medicine];[University of Miami];[Howard Hughes Medical Institute, St. Jude Children's Research Hospital];[National Institute on Aging];[Hadassah Medical Center];[University of Sheffield];[Southampton General Hospital, University of Southampton];[King's College Hospital, King's College London];[Johns Hopkins University, National Institute on Aging];[Institute of Psychiatry, Psychology and Neuroscience, King's College London, University of Auckland];[Columbia University];[Columbia University];[Harvard Medical School, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard Medical School, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research at Broad Institute]	4.32	55	Nature neuroscience	22	12	1966-1974
U01MH115727	Group 4	Genomics				GSE86153,GSE116470,GSE103723		phs000989.v3, phs000424.v8.p1		10.1038/s41586-019-1289-x	31168097	2019	Individual brain organoids reproducibly form cell diversity of the human cerebral cortex.	Experimental models of the human brain are needed for basic understanding of its development and disease1. Human brain organoids hold unprecedented promise for this purpose; however, they are plagued by high organoid-to-organoid variability2,3. This has raised doubts as to whether developmental processes of the human brain can occur outside the context of embryogenesis with a degree of reproducibility that is comparable to the endogenous tissue. Here we show that an organoid model of the dorsal forebrain can reliably generate a rich diversity of cell types appropriate for the human cerebral cortex. We performed single-cell RNA-sequencing analysis of 166,242 cells isolated from 21 individual organoids, finding that 95% of the organoids generate a virtually indistinguishable compendium of cell types, following similar developmental trajectories and with a degree of organoid-to-organoid variability comparable to that of individual endogenous brains. Furthermore, organoids derived from different stem cell lines show consistent reproducibility in the cell types produced. The data demonstrate that reproducible development of the complex cellular diversity of the central nervous system does not require the context of the embryo, and that establishment of terminal cell identity is a highly constrained process that can emerge from diverse stem cell origins and growth environments.	Cell Line;Cerebral Cortex;Female;Fetus;Humans;Induced Pluripotent Stem Cells;Male;Organoids;Prosencephalon;RNA-Seq;Reproducibility of Results;Single-Cell Analysis;Time Factors;Tissue Culture Techniques;Transcriptome	Brain;Cell Line;Cells;Central Nervous System;Cerebral Cortex;Comprehension;Disease;Embryo;Embryonic Development;Environment;Experimental Model;Female;Fetus;Form;Growth;Humans;Induced Pluripotent Stem Cells;Male;Organoids;Prosencephalon;RNA-Seq;Reproducibility of Results;Sequence Determinations, RNA;Single-Cell Analysis;Stem Cells;Time Factors;Tissue Culture Techniques;Tissues;Transcriptome		Velasco, Silvia;Kedaigle, Amanda J;Simmons, Sean K;Nash, Allison;Rocha, Marina;Quadrato, Giorgia;Paulsen, Bruna;Nguyen, Lan;Adiconis, Xian;Regev, Aviv;Levin, Joshua Z;Arlotta, Paola	[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, California Institute for Regenerative Medicine, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard];[Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Howard Hughes Medical Institute, Massachusetts Institute of Technology];[Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute]	23.54	305	Nature	570	7762	523-527
U01MH115727	Group 4					GSE157977				10.1126/science.aaz6063	33243861	2020	In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes.	The number of disease risk genes and loci identified through human genetic studies far outstrips the capacity to systematically study their functions. We applied a scalable genetic screening approach, in vivo Perturb-Seq, to functionally evaluate 35 autism spectrum disorder/neurodevelopmental delay (ASD/ND) de novo loss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshift mutations in these risk genes in pools, within the developing mouse brain in utero, followed by single-cell RNA-sequencing of perturbed cells in the postnatal brain. We identified cell type-specific and evolutionarily conserved gene modules from both neuronal and glial cell classes. Recurrent gene modules and cell types are affected across this cohort of perturbations, representing key cellular effects across sets of ASD/ND risk genes. In vivo Perturb-Seq allows us to investigate how diverse mutations affect cell types and states in the developing organism.	Animals;Ankyrins;Autistic Disorder;Brain;CRISPR-Cas Systems;DNA-Binding Proteins;Frameshift Mutation;Gene Expression Profiling;Genetic Loci;Humans;Mice;Neuroglia;Neurons;Repressor Proteins;Risk;Transcription Factors	Affect;Animals;Ankyrins;Autism Spectrum Disorder;Autistic Disorder;Brain;CRISPR-Cas Systems;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;DNA-Binding Proteins;Disease;Frameshift Mutation;Gene Expression Profiling;Gene Modules;Genes;Genetic Loci;Genetic Screening;Human Genetics;Humans;Mice;Mutation;Neuroglia;Neurons;Repressor Proteins;Risk;Sequence Determinations, RNA;Transcription Factors		Jin, Xin;Simmons, Sean K;Guo, Amy;Shetty, Ashwin S;Ko, Michelle;Nguyen, Lan;Jokhi, Vahbiz;Robinson, Elise;Oyler, Paul;Curry, Nathan;Deangeli, Giulio;Lodato, Simona;Levin, Joshua Z;Regev, Aviv;Zhang, Feng;Arlotta, Paola	[Broad Institute of MIT and Harvard, Harvard University, Massachusetts Institute of Technology];[Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University];[Broad Institute of MIT and Harvard];[Harvard University];[Broad Institute of MIT and Harvard, Harvard T.H. Chan School of Public Health, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University];[Harvard University];[Harvard University];[Humanitas Research Hospital, Humanitas University];[Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Howard Hughes Medical Institute];[Broad Institute of MIT and Harvard, Harvard University, Howard Hughes Medical Institute, Massachusetts Institute of Technology];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute]	3.45	38	Science (New York, N.Y.)	370	6520
U01MH115727	Group 4	Imaging								10.1016/j.devcel.2020.05.009	32516597	2020	Long-Range Optogenetic Control of Axon Guidance Overcomes Developmental Boundaries and Defects.	Axons connect neurons together, establishing the wiring architecture of neuronal networks. Axonal connectivity is largely built during embryonic development through highly constrained processes of axon guidance, which have been extensively studied. However, the inability to control axon guidance, and thus neuronal network architecture, has limited investigation of how axonal connections influence subsequent development and function of neuronal networks. Here, we use zebrafish motor neurons expressing a photoactivatable Rac1 to co-opt endogenous growth cone guidance machinery to precisely and non-invasively direct axon growth using light. Axons can be guided over large distances, within complex environments of living organisms, overriding competing endogenous signals and redirecting axons across potent repulsive barriers to construct novel circuitry. Notably, genetic axon guidance defects can be rescued, restoring functional connectivity. These data demonstrate that intrinsic growth cone guidance machinery can be co-opted to non-invasively build new connectivity, allowing investigation of neural network dynamics in intact living organisms.	Animals;Axon Guidance;Cells, Cultured;Motor Neurons;Optogenetics;Synapses;Zebrafish;Zebrafish Proteins;rac1 GTP-Binding Protein	Animals;Architecture;Axon Guidance;Axons;Cells, Cultured;Embryonic Development;Environment;Genetics;Growth;Growth Cones;Light;Motor Neurons;Nerve Regeneration;Neuronal Outgrowth;Neurons;News;Optogenetics;Synapses;Tissue Engineering;Zebrafish;Zebrafish Proteins;rac GTP-Binding Proteins;rac1 GTP-Binding Protein	axon guidance;axons;embryonic development;nerve regeneration;neuronal outgrowth;neurons;optogenetics;rac GTP-binding proteins;tissue engineering;zebrafish	Harris, James M;Wang, Andy Yu-Der;Boulanger-Weill, Jonathan;Santoriello, Cristina;Foianini, Stephan;Lichtman, Jeff W;Zon, Leonard I;Arlotta, Paola	[Broad Institute of MIT and Harvard, Harvard Medical School, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University];[Harvard University];[Dana-Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, Harvard University, Howard Hughes Medical Institute];[Harvard University];[Harvard University];[Dana-Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, Harvard University, Howard Hughes Medical Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute]	1.54	14	Developmental cell	53	5	577-588.e7
U01MH115727	Group 4									10.1176/appi.ajp.2020.20111608	33384012	2021	Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms.	Recent progress in the identification of genes and genomic regions contributing to autism spectrum disorder (ASD) has had a broad impact on our understanding of the nature of genetic risk for a range of psychiatric disorders, on our understanding of ASD biology, and on defining the key challenges now facing the field in efforts to translate gene discovery into an actionable understanding of pathology. While these advances have not yet had a transformative impact on clinical practice, there is nonetheless cause for real optimism: reliable lists of risk genes are large and growing rapidly; the identified encoded proteins have already begun to point to a relatively small number of areas of biology, where parallel advances in neuroscience and functional genomics are yielding profound insights; there is strong evidence pointing to mid-fetal prefrontal cortical development as one nexus of vulnerability for some of the largest-effect ASD risk genes; and there are multiple plausible paths forward toward rational therapeutics development that, while admittedly challenging, constitute fundamental departures from what was possible prior to the era of successful gene discovery.	Autism Spectrum Disorder;Genes;Genetic Predisposition to Disease;Humans	Autism Spectrum Disorder;Biology;Candidate Gene Identification;Comprehension;Genes;Genetic Predisposition to Disease;Genetics;Genomics;Humans;Mental Disorders;Nature;Neurodevelopmental Disorders;Neurosciences;Optimism;Pathology;Proteins;Risk;Therapeutics	Autism Spectrum Disorder;Genetics/Genomics;Neurodevelopmental Disorders	Manoli, Devanand S;State, Matthew W	[University of California, San Francisco];[University of California, San Francisco]	4.24	13	The American journal of psychiatry	178	1	30-38
U01MH115727	Group 4	Imaging								10.1016/j.xpro.2021.100947	34841275	2021	Optogenetic axon guidance in embryonic zebrafish.	Axons form the long-range connections of biological neuronal networks, which are built through the developmental process of axon guidance. Here, we describe a protocol to precisely and non-invasively control axonal growth trajectories in live zebrafish embryos using focal light activation of a photoactivatable Rac1. We outline techniques for photostimulation, time-lapse imaging, and immunohistochemistry. These approaches enable engineering of long-range axonal circuitry or repair of defective circuits in living zebrafish, despite a milieu of competing endogenous signals and repulsive barriers. For complete details on the use and execution of this protocol, please refer to Harris et al. (2020).	Animals;Axon Guidance;Embryo, Nonmammalian;Female;Image Processing, Computer-Assisted;Immunohistochemistry;Male;Optogenetics;Time-Lapse Imaging;Zebrafish	Animals;Axon Guidance;Axons;Biopharmaceuticals;Developmental Biology;Embryo;Embryo, Nonmammalian;Engineering;Female;Form;Growth;Image Processing, Computer-Assisted;Immunohistochemistry;Light;Male;Microscopy;Molecular Biology;Neurosciences;Optogenetics;Outline;Time-Lapse Imaging;Zebrafish	Developmental biology;Microscopy;Model Organisms;Molecular Biology;Neuroscience	Harris, James M;Yu-Der Wang, Andy;Arlotta, Paola	[Broad Institute of MIT and Harvard, Harvard Medical School, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Harvard University];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute]		1	STAR protocols	2	4	100947
U01MH115727	Group 4	Genomics	Synapse		Synapse::syn26346373,Single Cell Portal::SCP1129					10.1038/s41586-021-04358-6	35110736	2022	Autism genes converge on asynchronous development of shared neuron classes.	Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1-6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes-SUV420H1 (also known as KMT5B), ARID1B and CHD8-in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages-γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons-but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.	Autism Spectrum Disorder;Cerebral Cortex;DNA-Binding Proteins;GABAergic Neurons;Genetic Predisposition to Disease;Histone-Lysine N-Methyltransferase;Humans;Neurons;Organoids;Proteomics;RNA-Seq;Single-Cell Analysis;Transcription Factors	Autism Spectrum Disorder;Autistic Disorder;Biopharmaceuticals;Brain;Calcium;Cell Line;Cells;Cerebral Cortex;DNA-Binding Proteins;Donors;GABAergic Neurons;Genes;Genetic Predisposition to Disease;Genetics;Genomics;Haploinsufficiency;Histone-Lysine N-Methyltransferase;Humans;Mutation;Neurons;Organoids;Pathology;Phenotype;Projection;Proteomics;RNA, Small Cytoplasmic;RNA-Seq;Research;Risk;Sequence Determinations, RNA;Single-Cell Analysis;Transcription Factors;gamma-Aminobutyric Acid		Paulsen, Bruna;Velasco, Silvia;Kedaigle, Amanda J;Pigoni, Martina;Quadrato, Giorgia;Deo, Anthony J;Adiconis, Xian;Uzquiano, Ana;Sartore, Rafaela;Yang, Sung Min;Simmons, Sean K;Symvoulidis, Panagiotis;Kim, Kwanho;Tsafou, Kalliopi;Podury, Archana;Abbate, Catherine;Tucewicz, Ashley;Smith, Samantha N;Albanese, Alexandre;Barrett, Lindy;Sanjana, Neville E;Shi, Xi;Chung, Kwanghun;Lage, Kasper;Boyden, Edward S;Regev, Aviv;Levin, Joshua Z;Arlotta, Paola	[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Murdoch Children's Research Institute, Stanley Center for Psychiatric Research at Broad Institute, The Royal Children's Hospital Melbourne];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[California Institute for Regenerative Medicine, Harvard University, Keck School of Medicine, University of Southern California];[Boston Children's Hospital, Broad Institute of MIT and Harvard, Harvard Medical School, Harvard University, Robert Wood Johnson Medical School, Rutgers University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research at Broad Institute];[Massachusetts Institute of Technology];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research at Broad Institute];[Harvard Medical School, Harvard University, Massachusetts Institute of Technology];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Massachusetts Institute of Technology];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, New York Genome Center, New York University, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research at Broad Institute];[Massachusetts Institute of Technology, New York Genome Center];[Broad Institute of MIT and Harvard, Massachusetts General Hospital, Stanley Center for Psychiatric Research at Broad Institute];[Harvard Medical School, Harvard University, Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology];[Broad Institute of MIT and Harvard, Genentech, Massachusetts Institute of Technology];[Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute]		5	Nature	602	7896	268-273
U01MH115727	Group 4	Imaging								10.1093/biostatistics/kxaa047	33417699	2022	Dose-response modeling in high-throughput cancer drug screenings: an end-to-end approach.	Personalized cancer treatments based on the molecular profile of a patient's tumor are an emerging and exciting class of treatments in oncology. As genomic tumor profiling is becoming more common, targeted treatments for specific molecular alterations are gaining traction. To discover new potential therapeutics that may apply to broad classes of tumors matching some molecular pattern, experimentalists and pharmacologists rely on high-throughput, in vitro screens of many compounds against many different cell lines. We propose a hierarchical Bayesian model of how cancer cell lines respond to drugs in these experiments and develop a method for fitting the model to real-world high-throughput screening data. Through a case study, the model is shown to capture nontrivial associations between molecular features and drug response, such as requiring both wild type TP53 and overexpression of MDM2 to be sensitive to Nutlin-3(a). In quantitative benchmarks, the model outperforms a standard approach in biology, with $\approx20\%$ lower predictive error on held out data. When combined with a conditional randomization testing procedure, the model discovers markers of therapeutic response that recapitulate known biology and suggest new avenues for investigation. All code for the article is publicly available at https://github.com/tansey/deep-dose-response.	Antineoplastic Agents;Bayes Theorem;Drug Evaluation, Preclinical;Early Detection of Cancer;High-Throughput Screening Assays;Humans;Neoplasms	Antineoplastic Agents;Association;Bayes Theorem;Benchmarks;Biology;Cancer;Case Study;Cell Line;Deep Learning;Drug Discovery;Drug Evaluation, Preclinical;Early Detection of Cancer;Genomics;High-Throughput Screening;High-Throughput Screening Assays;Humans;In Vitro;Methods;Neoplasms;News;Patients;Pharmaceutical Preparations;Precision Medicine;Procedures;Random Allocation;Standards;Therapeutics;Traction	Deep learning;Dose–response modeling;Drug discovery;Empirical Bayes;High-throughput screening;Personalized medicine	Tansey, Wesley;Li, Kathy;Zhang, Haoran;Linderman, Scott W;Rabadan, Raul;Blei, David M;Wiggins, Chris H	[Memorial Sloan-Kettering Cancer Center];[Columbia University, Columbia University Medical Center];[Columbia University, Columbia University Medical Center];[Columbia University, Columbia University Medical Center];[Columbia University, Columbia University Medical Center];[Columbia University, Columbia University Medical Center];[Columbia University, Columbia University Medical Center]		2	Biostatistics (Oxford, England)	23	2	643-665
U01MH115727	Group 4	Review								10.1016/j.jmb.2021.167221	34474087	2022	Leveraging the Genetic Diversity of Human Stem Cells in Therapeutic Approaches.	Since their discovery 15 years ago, human pluripotent stem cell (hPSC) technologies have begun to revolutionize science and medicine, rapidly expanding beyond investigative research to drug discovery and development. Efforts to leverage hPSCs over the last decade have focused on increasing both the complexity and in vivo fidelity of human cellular models through enhanced differentiation methods. While these evolutions have fostered novel insights into disease mechanisms and influenced clinical drug discovery and development, there are still several considerations that limit the utility of hPSC models. In this review, we highlight important, yet underexplored avenues to broaden their reach. We focus on (i) the importance of diversifying existing hPSC collections, and their utilization to investigate therapeutic strategies in individuals from different genetic backgrounds, ancestry and sex; (ii) considerations for the selection of therapeutically relevant hPSC-based models; (iii) strategies to adequately increase the scale of cell-based studies; and (iv) the advances and constraints of clinical trials in a dish. Moreover, we advocate for harnessing the translational capabilities of hPSC models along with the use of innovative, scalable approaches for understanding genetic biases and the impact of sex and ancestry on disease mechanisms and drug efficacy and response. The next decade of hPSC innovation is poised to provide vast insights into the genetic basis of human disease and enable rapid advances to develop, repurpose, and ensure the safety of the next generation of disease therapies across diverse human populations.	Cell Differentiation;Genetic Variation;Humans;Pharmacogenomic Testing;Pluripotent Stem Cells	Bias;Cell Differentiation;Cells;Clinical Trial;Collection;Comprehension;Disease;Drug Discovery;Generations;Genetic Background;Genetic Variation;Genetics;Humans;Medicine;Methods;Pharmaceutical Preparations;Pharmacogenomic Testing;Pluripotent Stem Cells;Population;Research;Review;Safety;Scales;Science;Sex;Stem Cells;Technology;Therapeutics	ancestry;genetic diversity;iPSCs;sex;therapeutics	Tegtmeyer, Matthew;Nehme, Ralda	[Broad Institute of MIT and Harvard, Harvard University, King's College London, Stanley Center for Psychiatric Research at Broad Institute];[Broad Institute of MIT and Harvard, Harvard University, Stanley Center for Psychiatric Research at Broad Institute]		1	Journal of molecular biology	434	3	167221
U01MH115746	Group 5									10.1126/science.aat8127	30545856	2018	Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder.	Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.	Autism Spectrum Disorder;Bipolar Disorder;Brain;Genetic Predisposition to Disease;Humans;Protein Isoforms;RNA Splicing;Schizophrenia;Sequence Analysis, RNA;Transcriptome	Association;Astrocytes;Autism Spectrum Disorder;Bipolar Disorder;Brain;Disease;Exhibition;Gene Expression;Genetic Predisposition to Disease;Genetics;Genomics;Genotype;Humans;Interferons;Mental Disorders;Organizations;Pathology, Molecular;Protein Isoforms;RNA Splicing;Regulatory Sequences, Nucleic Acid;Resources;Risk;Schizophrenia;Sequence Analysis, RNA;Sequence Determinations, RNA;Therapeutics;Transcriptome;Work		Gandal, Michael J;Zhang, Pan;Hadjimichael, Evi;Walker, Rebecca L;Chen, Chao;Liu, Shuang;Won, Hyejung;van Bakel, Harm;Varghese, Merina;Wang, Yongjun;Shieh, Annie W;Haney, Jillian;Parhami, Sepideh;Belmont, Judson;Kim, Minsoo;Moran Losada, Patricia;Khan, Zenab;Mleczko, Justyna;Xia, Yan;Dai, Rujia;Wang, Daifeng;Yang, Yucheng T;Xu, Min;Fish, Kenneth;Hof, Patrick R;Warrell, Jonathan;Fitzgerald, Dominic;White, Kevin;Jaffe, Andrew E;;Peters, Mette A;Gerstein, Mark;Liu, Chunyu;Iakoucheva, Lilia M;Pinto, Dalila;Geschwind, Daniel H	;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;	23.84	400	Science (New York, N.Y.)	362	6420
U01MH115746	Group 5					GSE125697				10.1186/s13229-019-0278-0	31198525	2019	CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes.	CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed in Dup15q syndrome as well as autism spectrum disorder (ASD). While CYFIP1 heterozygosity has been rigorously studied due to its loss in 15q11.2 deletion, Prader-Willi and Angelman syndrome, the effects of CYFIP1 overexpression, as is observed in patients with CYFIP1 duplication, are less well understood. We developed and validated a mouse model of human CYFIP1 overexpression (CYFIP1 OE) using qPCR and western blot analysis. We performed a large battery of behavior testing on these mice, including ultrasonic vocalizations, three-chamber social assay, home-cage behavior, Y-maze, elevated plus maze, open field test, Morris water maze, fear conditioning, prepulse inhibition, and the hot plate assay. We also performed RNA sequencing and analysis on the basolateral amygdala. Extensive behavioral testing in CYFIP1 OE mice reveals no changes in the core behaviors related to ASD: social interactions and repetitive behaviors. However, we did observe mild learning deficits and an exaggerated fear response. Using RNA sequencing of the basolateral amygdala, a region associated with fear response, we observed changes in pathways related to cytoskeletal regulation, oligodendrocytes, and myelination. We also identified GABA-A subunit composition changes in basolateral amygdala neurons, which are essential components of the neural fear conditioning circuit. Overall, this research identifies the behavioral and molecular consequences of CYFIP1 overexpression and how they contribute to the variable phenotype seen in Dup15q syndrome and in ASD patients with excess CYFIP1.	Adaptor Proteins, Signal Transducing;Animals;Anxiety;Autism Spectrum Disorder;Basolateral Nuclear Complex;Behavior, Animal;Cytoskeleton;Fear;GABAergic Neurons;Humans;Intellectual Disability;Interneurons;Learning;Memory Disorders;Mice, Inbred C57BL;Myelin Sheath;Phenotype;Social Behavior	Actins;Adaptor Proteins, Signal Transducing;Affect;Angelman Syndrome;Animals;Anxiety;Autism Spectrum Disorder;Basolateral Nuclear Complex;Behavior;Behavior, Animal;Blot, Western;Cytoskeleton;Elevated Plus Maze Test;Fear;GABAergic Neurons;Humans;Intellectual Disability;Interneurons;Learning;Memory Disorders;Mice;Mice, Inbred C57BL;Morris Water Maze Test;Myelin Sheath;Neurodevelopmental Disorders;Neurons;Oligodendroglia;Open Field Test;Overall;Patients;Phenotype;Polymerase Chain Reaction;Prepulse Inhibition;Proteins;Regulation;Research;Sequence Determinations, RNA;Social Behavior;Social Interaction;Syndrome;Ultrasonics;gamma-Aminobutyric Acid	Autism spectrum disorder (ASD);CYFIP1;Dup15q;Fear conditioning;Mouse behavior;Neurodevelopmental disorders;RNA sequencing	Fricano-Kugler, Catherine;Gordon, Aaron;Shin, Grace;Gao, Kun;Nguyen, Jade;Berg, Jamee;Starks, Mary;Geschwind, Daniel H	[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles]	0.85	10	Molecular autism	10		25
U01MH115746	Group 5									10.1016/j.cell.2019.01.015	30901538	2019	Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders.	Studies of the genetics of psychiatric disorders have become one of the most exciting and fast-moving areas in human genetics. A decade ago, there were few reproducible findings, and now there are hundreds. In this review, we focus on the findings that have illuminated the genetic architecture of psychiatric disorders and the challenges of using these findings to inform our understanding of pathophysiology. The evidence is now overwhelming that psychiatric disorders are "polygenic"-that many genetic loci contribute to risk. With the exception of a subset of those with ASD, few individuals with a psychiatric disorder have a single, deterministic genetic cause; rather, developing a psychiatric disorder is influenced by hundreds of different genetic variants, consistent with a polygenic model. As progressively larger studies have uncovered more about their genetic architecture, the need to elucidate additional architectures has become clear. Even if we were to have complete knowledge of the genetic architecture of a psychiatric disorder, full understanding requires deep knowledge of the functional genomic architecture-the implicated loci impact regulatory processes that influence gene expression and the functional coordination of genes that control biological processes. Following from this is cellular architecture: of all brain regions, cell types, and developmental stages, where and when are the functional architectures operative? Given that the genetic architectures of different psychiatric disorders often strongly overlap, we are challenged to re-evaluate and refine the diagnostic architectures of psychiatric disorders using fundamental genetic and neurobiological data.	Alleles;Gene Frequency;Genetic Predisposition to Disease;Genetic Variation;Genome-Wide Association Study;Genomics;Humans;Mental Disorders;Mental Health;Multifactorial Inheritance	Alleles;Architecture;Biological Processes;Brain;Cells;Comprehension;Gene Expression;Gene Frequency;Genes;Genetic Loci;Genetic Predisposition to Disease;Genetic Variation;Genetics;Genome-Wide Association Study;Genomics;Human Genetics;Humans;Knowledge;Mental Disorders;Mental Health;Multifactorial Inheritance;Needs;Review;Risk		Sullivan, Patrick F;Geschwind, Daniel H	[Karolinska Institute, University of North Carolina, Chapel Hill];[David Geffen School of Medicine, University of California, Los Angeles]	10.87	145	Cell	177	1	162-183
U01MH115745	Group 5					GSE115011				10.1038/s41593-018-0316-9	30692691	2019	Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures.	Investigating human oligodendrogenesis and the interaction of oligodendrocytes with neurons and astrocytes would accelerate our understanding of the mechanisms underlying white matter disorders. However, this is challenging because of the limited accessibility of functional human brain tissue. Here, we developed a new differentiation method of human induced pluripotent stem cells to generate three-dimensional brain organoids that contain oligodendrocytes as well as neurons and astrocytes, called human oligodendrocyte spheroids. We found that oligodendrocyte lineage cells derived in human oligodendrocyte spheroids transitioned through developmental stages similar to primary human oligodendrocytes and that the migration of oligodendrocyte lineage cells and their susceptibility to lysolecithin exposure could be captured by live imaging. Moreover, their morphology changed as they matured over time in vitro and started myelinating neurons. We anticipate that this method can be used to study oligodendrocyte development, myelination, and interactions with other major cell types in the CNS.	Astrocytes;Cell Culture Techniques;Cell Differentiation;Cell Line;Cell Lineage;Humans;Induced Pluripotent Stem Cells;Neurons;Oligodendroglia;Spheroids, Cellular;Transcriptome	Astrocytes;Brain;Cell Culture Techniques;Cell Differentiation;Cell Line;Cell Lineage;Cells;Comprehension;Culture;Human Induced Pluripotent Stem Cells;Humans;In Vitro;Induced Pluripotent Stem Cells;Lysophosphatidylcholines;Methods;Neurons;News;Oligodendroglia;Organoids;Spheroids, Cellular;Time;Tissues;Transcriptome;White Matter		Marton, Rebecca M;Miura, Yuki;Sloan, Steven A;Li, Qingyun;Revah, Omer;Levy, Rebecca J;Huguenard, John R;Pașca, Sergiu P	[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine]	10.66	135	Nature neuroscience	22	3	484-491
U01MH115746	Group 5									10.1016/j.celrep.2019.05.006	31141683	2019	Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism.	Loss-of-function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder in humans and produce social deficits, repetitive behaviors, and seizures in mice. However, the functional effects of these mutations at cellular and circuit levels remain elusive. Using laser-scanning photostimulation, whole-cell recordings, and electron microscopy, we found a dramatic decrease in excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons of the medial prefrontal cortex (mPFC) of Cntnap2 knockout (KO) mice, concurrent with reduced spines and synapses, despite normal dendritic complexity and intrinsic excitability. Moreover, recording of mPFC local field potentials (LFPs) and unit spiking in vivo revealed increased activity in inhibitory neurons, reduced phase-locking to delta and theta oscillations, and delayed phase preference during locomotion. Excitatory neurons showed similar phase modulation changes at delta frequencies. Finally, pairwise correlations increased during immobility in KO mice. Thus, reduced synaptic inputs can yield perturbed temporal coordination of neuronal firing in cortical ensembles.	Animals;Autistic Disorder;Dendrites;Disease Models, Animal;Excitatory Postsynaptic Potentials;Female;Male;Membrane Proteins;Mice;Mice, Inbred C57BL;Mice, Knockout;Nerve Tissue Proteins;Prefrontal Cortex;Pyramidal Cells;Synapses	Animals;Autism Spectrum Disorder;Autistic Disorder;Behavior;Biomarkers;Brain;Dendrites;Disease Models, Animal;Electroencephalography;Excitatory Postsynaptic Potentials;Female;Form;Humans;Lasers;Locomotion;Loss of Function Mutation;Male;Membrane Proteins;Mice;Mice, Inbred C57BL;Mice, Knockout;Microscopy, Electron;Mutation;Nerve Tissue Proteins;Neurons;Population Dynamics;Prefrontal Cortex;Pyramidal Cells;Seizures;Spine;Synapses;Whole-Cell Recording	EEG;biomarker;brain state;connectivity;delta;functional;inhibition;oscillation;phase-locking;theta	Lazaro, Maria T;Taxidis, Jiannis;Shuman, Tristan;Bachmutsky, Iris;Ikrar, Taruna;Santos, Rommel;Marcello, G Mark;Mylavarapu, Apoorva;Chandra, Swasty;Foreman, Allison;Goli, Rachna;Tran, Duy;Sharma, Nikhil;Azhdam, Michelle;Dong, Hongmei;Choe, Katrina Y;Peñagarikano, Olga;Masmanidis, Sotiris C;Rácz, Bence;Xu, Xiangmin;Geschwind, Daniel H;Golshani, Peyman	[David Geffen School of Medicine, University of California, Los Angeles];[Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles];[Brain Research Institute, David Geffen School of Medicine, Icahn School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[University of California, Irvine];[University of California, Irvine];[University of Veterinary Medicine Budapest];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[University of California, Los Angeles];[CIBERER, CIBERSAM, University of the Basque Country];[Brain Research Institute, University of California, Los Angeles];[University of Veterinary Medicine Budapest];[University of California, Irvine];[David Geffen School of Medicine, University of California, Los Angeles];[Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, West Los Angeles VA Medical Center]	2.71	34	Cell reports	27	9	2567-2578.e6
U01MH115745;U01MH115746	Group 5									10.1038/s41592-018-0255-0	30573846	2019	Reliability of human cortical organoid generation.	The differentiation of pluripotent stem cells in three-dimensional cultures can recapitulate key aspects of brain development, but protocols are prone to variable results. Here we differentiated multiple human pluripotent stem cell lines for over 100 d using our previously developed approach to generate brain-region-specific organoids called cortical spheroids and, using several assays, found that spheroid generation was highly reliable and consistent. We anticipate the use of this approach for large-scale differentiation experiments and disease modeling.	Cell Line;Humans;Organoids;Pluripotent Stem Cells;Prosencephalon;Reproducibility of Results;Sequence Analysis, RNA;Single-Cell Analysis;Tissue Engineering	Brain;Cell Line;Culture;Disease;Generations;Humans;Organoids;Pluripotent Stem Cells;Prosencephalon;Reproducibility of Results;Scales;Sequence Analysis, RNA;Single-Cell Analysis;Tissue Engineering		Yoon, Se-Jin;Elahi, Lubayna S;Pașca, Anca M;Marton, Rebecca M;Gordon, Aaron;Revah, Omer;Miura, Yuki;Walczak, Elisabeth M;Holdgate, Gwendolyn M;Fan, H Christina;Huguenard, John R;Geschwind, Daniel H;Pașca, Sergiu P	[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];[David Geffen School of Medicine, University of California, Los Angeles];[Stanford University, Stanford University School of Medicine];[Stanford University, Stanford University School of Medicine];;;;[Stanford University, Stanford University School of Medicine];[David Geffen School of Medicine, University of California, Los Angeles];[Stanford University, Stanford University School of Medicine]	12.13	167	Nature methods	16	1	75-78
U01MH115745	Group 5					GSE132403				10.1126/science.aay1645	31974223	2020	Chromatin accessibility dynamics in a model of human forebrain development.	Forebrain development is characterized by highly synchronized cellular processes, which, if perturbed, can cause disease. To chart the regulatory activity underlying these events, we generated a map of accessible chromatin in human three-dimensional forebrain organoids. To capture corticogenesis, we sampled glial and neuronal lineages from dorsal or ventral forebrain organoids over 20 months in vitro. Active chromatin regions identified in human primary brain tissue were observed in organoids at different developmental stages. We used this resource to map genetic risk for disease and to explore evolutionary conservation. Moreover, we integrated chromatin accessibility with transcriptomics to identify putative enhancer-gene linkages and transcription factors that regulate human corticogenesis. Overall, this platform brings insights into gene-regulatory dynamics at previously inaccessible stages of human forebrain development, including signatures of neuropsychiatric disorders.	Animals;Cell Lineage;Chromatin;Chromatin Assembly and Disassembly;Gene Expression Regulation, Developmental;Humans;Mental Disorders;Mice;Nervous System Diseases;Neurogenesis;Organoids;Pluripotent Stem Cells;Prosencephalon;Transcriptome	Animals;Brain;Cell Lineage;Chart;Chromatin;Chromatin Assembly and Disassembly;Disease;Gene Expression Regulation, Developmental;Genes;Genes, Regulator;Genetics;Humans;In Vitro;Map;Mental Disorders;Mice;Nervous System Diseases;Neurogenesis;Organoids;Overall;Pluripotent Stem Cells;Prosencephalon;Resources;Risk;Tissues;Transcription Factors;Transcriptome		Trevino, Alexandro E;Sinnott-Armstrong, Nasa;Andersen, Jimena;Yoon, Se-Jin;Huber, Nina;Pritchard, Jonathan K;Chang, Howard Y;Greenleaf, William J;Pașca, Sergiu P	[Stanford University];[Stanford University];[Stanford University];[Stanford University];[Stanford University];[Howard Hughes Medical Institute, Stanford University];[Howard Hughes Medical Institute, Stanford University];[BioHub, Stanford University];[Stanford University]	6.05	60	Science (New York, N.Y.)	367	6476
U01MH115746	Group 5									10.1016/j.gde.2020.05.032	32634676	2020	Functional genomics links genetic origins to pathophysiology in neurodegenerative and neuropsychiatric disease.	Neurodegenerative and neuropsychiatric disorders are pervasive and debilitating conditions characterized by diverse clinical syndromes and comorbidities, whose origins are as complex and heterogeneous as their associated phenotypes. Risk for these disorders involves substantial genetic liability, which has fueled large-scale genetic studies that have led to a flood of discoveries. In turn, these discoveries have exposed substantial gaps in our knowledge with regards to the complicated genetic architecture of each disorder and the substantial amount of genetic overlap among disorders, which implies some degree of shared pathophysiology underlying these clinically distinct, multifactorial disorders. Understanding the role of specific genetic variants will involve resolving the connections between molecular pathways, heterogeneous cell types, specific circuits and disease pathogenesis at the tissue and patient level. We consider the current known genetic basis of these disorders and highlight the utility of molecular systems approaches that establish the function of genetic variation in the context of specific neurobiological networks, cell-types, and life stages. Beyond expanding our knowledge of disease mechanisms, understanding these relationships provides promise for early detection and potential therapeutic interventions.	Animals;Gene Expression Regulation;Genetic Predisposition to Disease;Genomics;Humans;Mental Disorders;Neurodegenerative Diseases;Polymorphism, Single Nucleotide	Animals;Architecture;Cells;Comorbidity;Comprehension;Disease;Floods;Gene Expression Regulation;Genetic Predisposition to Disease;Genetic Variation;Genetics;Genomics;Humans;Knowledge;Life;Mental Disorders;Neurodegenerative Diseases;Patients;Phenotype;Polymorphism, Single Nucleotide;Risk;Role;Scales;Syndrome;Therapeutics;Tissues		Wamsley, Brie;Geschwind, Daniel H	[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles]	0.30	3	Current opinion in genetics & development	65		117-125
U01MH115746	Group 5									10.1186/s13229-020-00332-7	32299488	2020	Human in vitro models for understanding mechanisms of autism spectrum disorder.	Early brain development is a critical epoch for the development of autism spectrum disorder (ASD). In vivo animal models have, until recently, been the principal tool used to study early brain development and the changes occurring in neurodevelopmental disorders such as ASD. In vitro models of brain development represent a significant advance in the field. Here, we review the main methods available to study human brain development in vitro and the applications of these models for studying ASD and other psychiatric disorders. We discuss the main findings from stem cell models to date focusing on cell cycle and proliferation, cell death, cell differentiation and maturation, and neuronal signaling and synaptic stimuli. To be able to generalize the results from these studies, we propose a framework of experimental design and power considerations for using in vitro models to study ASD. These include both technical issues such as reproducibility and power analysis and conceptual issues such as the brain region and cell types being modeled.	Animals;Autism Spectrum Disorder;Brain;Humans;Models, Biological;Stem Cells	Animals;Autism Spectrum Disorder;Brain;Cell Cycle;Cell Death;Cell Proliferation;Cells;Comprehension;Dates;Experimental Design;Humans;In Vitro;Mental Disorders;Methods;Models, Animal;Models, Biological;Neurodevelopmental Disorders;Power, Psychological;Review;Stem Cells		Gordon, Aaron;Geschwind, Daniel H	[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles]	0.99	8	Molecular autism	11	1	26
U01MH115746	Group 5									10.1038/s41467-020-18526-1	32978376	2020	Integrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism.	Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous neurodevelopmental disorder. Despite this heterogeneity, previous studies have shown patterns of molecular convergence in post-mortem brain tissue from autistic subjects. Here, we integrate genome-wide measures of mRNA expression, miRNA expression, DNA methylation, and histone acetylation from ASD and control brains to identify a convergent molecular subtype of ASD with shared dysregulation across both the epigenome and transcriptome. Focusing on this convergent subtype, we substantially expand the repertoire of differentially expressed genes in ASD and identify a component of upregulated immune processes that are associated with hypomethylation. We utilize eQTL and chromosome conformation datasets to link differentially acetylated regions with their cognate genes and identify an enrichment of ASD genetic risk variants in hyperacetylated noncoding regulatory regions linked to neuronal genes. These findings help elucidate how diverse genetic risk factors converge onto specific molecular processes in ASD.	Autism Spectrum Disorder;Brain;DNA Methylation;Epigenomics;Gene Expression Regulation;Gene Regulatory Networks;Genomics;Histones;Humans;MicroRNAs;RNA, Messenger;Transcriptome	Acetylation;Autism Spectrum Disorder;Autistic Disorder;Brain;Chromosomes;DNA Methylation;Dataset;Epigenome;Epigenomics;Gene Expression Regulation;Gene Regulatory Networks;Genes;Genetics;Genome;Genomics;Histones;Humans;Immunity;Measures;MicroRNAs;Neurodevelopmental Disorders;RNA, Messenger;Regulatory Sequences, Nucleic Acid;Risk;Risk Factors;Tissues;Transcriptome		Ramaswami, Gokul;Won, Hyejung;Gandal, Michael J;Haney, Jillian;Wang, Jerry C;Wong, Chloe C Y;Sun, Wenjie;Prabhakar, Shyam;Mill, Jonathan;Geschwind, Daniel H	[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles, University of North Carolina, Chapel Hill];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[Institute of Psychiatry, Psychology and Neuroscience, King's College London];[Genome Institute of Singapore];[Genome Institute of Singapore];[University of Exeter, University of Exeter Medical School];[David Geffen School of Medicine, University of California, Los Angeles]	2.62	21	Nature communications	11	1	4873
U01MH115745;U01MH115746	Group 5					GSE142041,GSE145122				10.1038/s41591-020-1043-9	32989314	2020	Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.	22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.	Adult;Calcium Signaling;Cell Differentiation;Cerebral Cortex;DiGeorge Syndrome;Female;Humans;Induced Pluripotent Stem Cells;Male;Neurons;Organoids;Young Adult	Adult;Antipsychotic Agents;Calcium;Calcium Channels;Calcium Signaling;Cell Differentiation;Cerebral Cortex;DiGeorge Syndrome;Disease;Electrophysiology;Female;Form;Genes;Genetics;Humans;Induced Pluripotent Stem Cells;Male;Neurons;Organoids;Phenotype;Resting Potentials;Stem Cells;Velocardiofacial Syndrome;Young Adult		Khan, Themasap A;Revah, Omer;Gordon, Aaron;Yoon, Se-Jin;Krawisz, Anna K;Goold, Carleton;Sun, Yishan;Kim, Chul Hoon;Tian, Yuan;Li, Min-Yin;Schaepe, Julia M;Ikeda, Kazuya;Amin, Neal D;Sakai, Noriaki;Yazawa, Masayuki;Kushan, Leila;Nishino, Seiji;Porteus, Matthew H;Rapoport, Judith L;Bernstein, Jonathan A;O'Hara, Ruth;Bearden, Carrie E;Hallmayer, Joachim F;Huguenard, John R;Geschwind, Daniel H;Dolmetsch, Ricardo E;Paşca, Sergiu P	[Stanford University];[Stanford University];[University of California, Los Angeles];[Stanford University];[Beth Israel Deaconess Medical Center, Stanford University];[Stanford University];[Stanford University];[Stanford University, Yonsei University College of Medicine];[University of California, Los Angeles];[Stanford University];[Stanford University];[Stanford University];[Stanford University];[Stanford University];[Columbia University, Stanford University];[University of California, Los Angeles];[Stanford University];[Stanford University];[Child Psychiatry Branch, National Institute of Mental Health];[Stanford University];[Stanford University];[Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles];[Stanford University];[Stanford University];[David Geffen School of Medicine, University of California, Los Angeles];[Novartis AG];[Stanford University]	3.00	28	Nature medicine	26	12	1888-1898
U01MH115746	Group 5									10.1038/s41593-021-00871-z	34183867	2021	Enhanced hippocampal theta rhythmicity and emergence of eta oscillation in virtual reality.	Hippocampal theta rhythm is a therapeutic target because of its vital role in neuroplasticity, learning and memory. Curiously, theta differs across species. Here we show that theta rhythmicity is greatly amplified when rats run in virtual reality. A novel eta rhythm emerged in the CA1 cell layer, primarily in interneurons. Thus, multisensory experience governs hippocampal rhythms. Virtual reality can be used to boost or control brain rhythms and to alter neural dynamics, wiring and plasticity.	Animals;Brain Waves;Hippocampus;Male;Rats;Rats, Long-Evans;Virtual Reality	Animals;Brain;Brain Waves;Cells;Hippocampus;Interneurons;Learning;Male;Memory;Neuronal Plasticity;Periodicity;Rats;Rats, Long-Evans;Role;Therapeutics;Theta Rhythm;Virtual Reality		Safaryan, Karen;Mehta, Mayank R	[University of California, Los Angeles];[UCLA Brain Research Institute, University of California, Los Angeles]		3	Nature neuroscience	24	8	1065-1070
U01MH115746	Group 5									10.1186/s13059-020-02257-z	33514394	2021	Evolutionary conservation and divergence of the human brain transcriptome.	Mouse models have allowed for the direct interrogation of genetic effects on molecular, physiological, and behavioral brain phenotypes. However, it is unknown to what extent neurological or psychiatric traits may be human- or primate-specific and therefore which components can be faithfully recapitulated in mouse models. We compare conservation of co-expression in 116 independent data sets derived from human, mouse, and non-human primate representing more than 15,000 total samples. We observe greater changes occurring on the human lineage than mouse, and substantial regional variation that highlights cerebral cortex as the most diverged region. Glia, notably microglia, astrocytes, and oligodendrocytes are the most divergent cell type, three times more on average than neurons. We show that cis-regulatory sequence divergence explains a significant fraction of co-expression divergence. Moreover, protein coding sequence constraint parallels co-expression conservation, such that genes with loss of function intolerance are enriched in neuronal, rather than glial modules. We identify dozens of human neuropsychiatric and neurodegenerative disease risk genes, such as COMT, PSEN-1, LRRK2, SHANK3, and SNCA, with highly divergent co-expression between mouse and human and show that 3D human brain organoids recapitulate in vivo co-expression modules representing several human cell types. We identify robust co-expression modules reflecting whole-brain and regional patterns of gene expression. Compared with those that represent basic metabolic processes, cell-type-specific modules, most prominently glial modules, are the most divergent between species. These data and analyses serve as a foundational resource to guide human disease modeling and its interpretation.	Animals;Astrocytes;Brain;Catechol O-Methyltransferase;Cerebral Cortex;Evolution, Molecular;Gene Expression Profiling;Humans;Leucine-Rich Repeat Serine-Threonine Protein Kinase-2;Mice;Microfilament Proteins;Nerve Tissue Proteins;Neurodegenerative Diseases;Neurons;Presenilin-1;Primates;Transcriptome;alpha-Synuclein	Animals;Astrocytes;Brain;Catechol O-Methyltransferase;Cells;Cerebral Cortex;Coding;Dataset;Disease;Evolution, Molecular;Gene Expression;Gene Expression Profiling;Genes;Genetics;Genomics;Humans;Leucine-Rich Repeat Serine-Threonine Protein Kinase-2;Metabolism;Mice;Microfilament Proteins;Microglia;Nerve Tissue Proteins;Neurodegenerative Diseases;Neuroglia;Neurons;Neurosciences;Oligodendroglia;Organoids;Phenotype;Presenilin-1;Primates;Proteins;Resources;Risk;Time;Transcriptome;alpha-Synuclein	Co-expression;Disease;Evolution;Genomics;Neuroscience;Transcriptome	Pembroke, William G;Hartl, Christopher L;Geschwind, Daniel H	[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles]	2.42	7	Genome biology	22	1	52
U01MH115745;U01MH115746	Group 5									10.1038/s41593-021-00802-y	33619405	2021	Long-term maturation of human cortical organoids matches key early postnatal transitions.	Human stem-cell-derived models provide the promise of accelerating our understanding of brain disorders, but not knowing whether they possess the ability to mature beyond mid- to late-fetal stages potentially limits their utility. We leveraged a directed differentiation protocol to comprehensively assess maturation in vitro. Based on genome-wide analysis of the epigenetic clock and transcriptomics, as well as RNA editing, we observe that three-dimensional human cortical organoids reach postnatal stages between 250 and 300 days, a timeline paralleling in vivo development. We demonstrate the presence of several known developmental milestones, including switches in the histone deacetylase complex and NMDA receptor subunits, which we confirm at the protein and physiological levels. These results suggest that important components of an intrinsic in vivo developmental program persist in vitro. We further map neurodevelopmental and neurodegenerative disease risk genes onto in vitro gene expression trajectories to provide a resource and webtool (Gene Expression in Cortical Organoids, GECO) to guide disease modeling.	Cell Differentiation;DNA Methylation;Gene Regulatory Networks;Humans;In Vitro Techniques;Induced Pluripotent Stem Cells;Neurodegenerative Diseases;Organoids	Ability;Brain Diseases;Cell Differentiation;Comprehension;DNA Methylation;Disease;Epigenetics;Gene Expression;Gene Regulatory Networks;Genes;Genome;Histone Deacetylase Complexes;Humans;In Vitro;In Vitro Techniques;Induced Pluripotent Stem Cells;Map;Neurodegenerative Diseases;Organoids;Program;Proteins;RNA Editing;Receptors, N-Methyl-D-Aspartate;Resources;Risk;Stem Cells		Gordon, Aaron;Yoon, Se-Jin;Tran, Stephen S;Makinson, Christopher D;Park, Jin Young;Andersen, Jimena;Valencia, Alfredo M;Horvath, Steve;Xiao, Xinshu;Huguenard, John R;Pașca, Sergiu P;Geschwind, Daniel H	[David Geffen School of Medicine, University of California, Los Angeles];[Stanford University];[University of California, Los Angeles, University of California, San Diego];[Stanford University, Stanford University School of Medicine];[Stanford University];[Stanford University];[Stanford University];[David Geffen School of Medicine, University of California, Los Angeles];[UCLA Molecular Biology Institute, University of California, Los Angeles];[Stanford University, Stanford University School of Medicine];[Stanford University];[David Geffen School of Medicine, University of California, Los Angeles]	10.90	38	Nature neuroscience	24	3	331-342
U01MH115746	Group 5									10.1016/j.biopsych.2020.10.002	33272361	2021	Polygenicity in Psychiatry-Like It or Not, We Have to Understand It.		Multifactorial Inheritance;Psychiatry	Multifactorial Inheritance;Psychiatry		Gandal, Michael J;Geschwind, Daniel H	[David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles];[David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles]		2	Biological psychiatry	89	1	2-4
U01MH115746	Group 5					GSE129891				10.1038/s41380-019-0576-0	31705054	2021	Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations.	Genetic risk for psychiatric illness is complex, so identification of shared molecular pathways where distinct forms of genetic risk might coincide is of substantial interest. A growing body of genetic and genomic studies suggest that such shared molecular pathways exist across disorders with different clinical presentations, such as schizophrenia and autism spectrum disorder (ASD). But how this relates to specific genetic risk factors is unknown. Further, whether some of the molecular changes identified in brain relate to potentially confounding antemortem or postmortem factors are difficult to prove. We analyzed the transcriptome from the cortex and hippocampus of three mouse lines modeling human copy number variants (CNVs) associated with schizophrenia and ASD: Df(h15q13)/+, Df(h22q11)/+, and Df(h1q21)/+ which carry the 15q13.3 deletion, 22q11.2 deletion, and 1q21.1 deletion, respectively. Although we found very little overlap of differential expression at the level of individual genes, gene network analysis identified two cortical and two hippocampal modules of co-expressed genes that were dysregulated across all three mouse models. One cortical module was associated with neuronal energetics and firing rate, and overlapped with changes identified in postmortem human brain from SCZ and ASD patients. These data highlight aspects of convergent gene expression in mouse models harboring major risk alleles, and strengthen the connection between changes in neuronal energetics and neuropsychiatric disorders in humans.	Animals;Autism Spectrum Disorder;Autistic Disorder;Chromosome Deletion;Humans;Mice;Schizophrenia;Transcriptome	Alleles;Animals;Autism Spectrum Disorder;Autistic Disorder;Brain;Chromosome Deletion;Form;Gene Expression;Gene Regulatory Networks;Genes;Genetics;Genomics;Hippocampus;Humans;Mental Disorders;Mice;Mutation;Patients;Risk;Risk Factors;Schizophrenia;Transcriptome		Gordon, Aaron;Forsingdal, Annika;Klewe, Ib Vestergaard;Nielsen, Jacob;Didriksen, Michael;Werge, Thomas;Geschwind, Daniel H	[University of California, Los Angeles];[Capital Region of Denmark, H. Lundbeck A/S];[H. Lundbeck A/S];[H. Lundbeck A/S];[H. Lundbeck A/S];[Capital Region of Denmark, H. Lundbeck A/S, Natural History Museum of Denmark, University of Copenhagen];[David Geffen School of Medicine, University of California, Los Angeles]	3.94	13	Molecular psychiatry	26	5	1520-1534
U01MH115746	Group 5	Genomics			Synapse::syn4587615					10.1038/s41467-022-31053-5	35680911	2022	Association between resting-state functional brain connectivity and gene expression is altered in autism spectrum disorder.	Gene expression covaries with brain activity as measured by resting state functional magnetic resonance imaging (MRI). However, it is unclear how genomic differences driven by disease state can affect this relationship. Here, we integrate from the ABIDE I and II imaging cohorts with datasets of gene expression in brains of neurotypical individuals and individuals with autism spectrum disorder (ASD) with regionally matched brain activity measurements from fMRI datasets. We identify genes linked with brain activity whose association is disrupted in ASD. We identified a subset of genes that showed a differential developmental trajectory in individuals with ASD compared with controls. These genes are enriched in voltage-gated ion channels and inhibitory neurons, pointing to excitation-inhibition imbalance in ASD. We further assessed differences at the regional level showing that the primary visual cortex is the most affected region in ASD. Our results link disrupted brain expression patterns of individuals with ASD to brain activity and show developmental, cell type, and regional enrichment of activity linked genes.	Autism Spectrum Disorder;Brain;Brain Mapping;Gene Expression;Humans;Magnetic Resonance Imaging;Neural Pathways	Affect;Association;Autism Spectrum Disorder;Brain;Brain Mapping;Cells;Dataset;Disease;Gene Expression;Genes;Genomics;Humans;Ion Channels;Magnetic Resonance Imaging;Neural Pathways;Neurons;Striate Cortex;fMRI		Berto, Stefano;Treacher, Alex H;Caglayan, Emre;Luo, Danni;Haney, Jillian R;Gandal, Michael J;Geschwind, Daniel H;Montillo, Albert A;Konopka, Genevieve	[UT Southwestern Medical Center];[UT Southwestern Medical Center];[UT Southwestern Medical Center];[UT Southwestern Medical Center];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[UT Southwestern Medical Center];[UT Southwestern Medical Center]			Nature communications	13	1	3328
U01MH115746	Group 5	Electrophysiology								10.1038/s41586-022-04404-x	35140401	2022	Moving bar of light evokes vectorial spatial selectivity in the immobile rat hippocampus.	Visual cortical neurons encode the position and motion direction of specific stimuli retrospectively, without any locomotion or task demand1. The hippocampus, which is a part of the visual system, is hypothesized to require self-motion or a cognitive task to generate allocentric spatial selectivity that is scalar, abstract2,3 and prospective4-7. Here we measured rodent hippocampal selectivity to a moving bar of light in a body-fixed rat to bridge these seeming disparities. About 70% of dorsal CA1 neurons showed stable activity modulation as a function of the angular position of the bar, independent of behaviour and rewards. One-third of tuned cells also encoded the direction of revolution. In other experiments, neurons encoded the distance of the bar, with preference for approaching motion. Collectively, these demonstrate visually evoked vectorial selectivity (VEVS). Unlike place cells, VEVS was retrospective. Changes in the visual stimulus or its predictability did not cause remapping but only caused gradual changes. Most VEVS-tuned neurons behaved like place cells during spatial exploration and the two selectivities were correlated. Thus, VEVS could form the basic building block of hippocampal activity. When combined with self-motion, reward or multisensory stimuli8, it can generate the complexity of prospective representations including allocentric space9, time10,11 and episodes12.	Animals;CA1 Region, Hippocampal;Hippocampus;Light;Neurons;Rats;Space Perception;Spatial Processing;Visual Cortex	Abstracts;Animals;Behavior;CA1 Region, Hippocampal;Cells;Form;Hippocampus;Light;Locomotion;Motion;Neurons;Place Cells;Rats;Reward;Rodentia;Self;Space Perception;Spatial Processing;Time;Visual Cortex		Purandare, Chinmay S;Dhingra, Shonali;Rios, Rodrigo;Vuong, Cliff;To, Thuc;Hachisuka, Ayaka;Choudhary, Krishna;Mehta, Mayank R	[University of California, Los Angeles];[University of California, Los Angeles];[University of California, Los Angeles];[University of California, Los Angeles];[University of California, Los Angeles];[University of California, Los Angeles];[University of California, Los Angeles];[University of California, Los Angeles]		0	Nature	602	7897	461-467
U01MH115746	Group 5	Electrophysiology								10.1016/j.neuroscience.2022.01.019	35121078	2022	Properties and Computational Consequences of Fast Dendritic Spikes during Natural Behavior.	The dendritic membrane potential was recently measured for the first time in drug-free, naturally behaving rats over several days. These showed that neuronal dendrites generate a lot of sodium spikes, up to ten times as many as the somatic spikes. These key experimental findings are reviewed here, along with a discussion of computational models, and computational consequences of such intense spike traffic in dendrites. We overview the experimental techniques that enabled these measurements as well as a variety of models, ranging from conceptual models to detailed biophysical models. The biophysical models suggest that the intense dendritic spiking activity can arise from the biophysical properties of the dendritic voltage-dependent and synaptic ion channels, and delineate some computational consequences of fast dendritic spike activity. One remarkable aspect is that in the model, with fast dendritic spikes, the efficacy of synaptic strength in terms of driving the somatic activity is much less dependent on the position of the synapse in dendrites. This property suggests that fast dendritic spikes is a way to confer to neurons the possibility to grow complex dendritic trees with little computational loss for the distal most synapses, and thus form very complex networks with high density of connections, such as typically in the human brain. Another important consequence is that dendritically localized spikes can allow simultaneous but different computations on different dendritic branches, thereby greatly increasing the computational capacity and complexity of neuronal networks.	Action Potentials;Animals;Dendrites;Membrane Potentials;Neurons;Pyramidal Cells;Rats;Synapses	Action Potentials;Animals;Behavior;Brain;Cerebral Cortex;Dendrites;Form;Humans;Ion Channels;Membrane Potentials;Neurons;Pharmaceutical Preparations;Pyramidal Cells;Rats;Sodium;Synapses;Time;Trees	Cerebral cortex;Computational model;Dendritic recording;Dendritic spikes;Extracellular recording;In vivo	Destexhe, Alain;Mehta, Mayank	[National Center for Scientific Research (France), University of Paris-Saclay];[University of California, Los Angeles]		1	Neuroscience	489		251-261
U01MH115746;U01MH121499	Group 5; Group 7									10.1038/s41593-021-00887-5	34294919	2021	Coexpression network architecture reveals the brain-wide and multiregional basis of disease susceptibility.	Gene networks have yielded numerous neurobiological insights, yet an integrated view across brain regions is lacking. We leverage RNA sequencing in 864 samples representing 12 brain regions to robustly identify 12 brain-wide, 50 cross-regional and 114 region-specific coexpression modules. Nearly 40% of genes fall into brain-wide modules, while 25% comprise region-specific modules reflecting regional biology, such as oxytocin signaling in the hypothalamus, or addiction pathways in the nucleus accumbens. Schizophrenia and autism genetic risk are enriched in brain-wide and multiregional modules, indicative of broad impact; these modules implicate neuronal proliferation and activity-dependent processes, including endocytosis and splicing, in disease pathophysiology. We find that cell-type-specific long noncoding RNA and gene isoforms contribute substantially to regional synaptic diversity and that constrained, mutation-intolerant genes are primarily enriched in neurons. We leverage these data using an omnigenic-inspired network framework to characterize how coexpression and gene regulatory networks reflect neuropsychiatric disease risk, supporting polygenic models.	Brain;Gene Expression Profiling;Gene Regulatory Networks;Genetic Predisposition to Disease;Humans;Mental Disorders;Transcriptome	Accidental Falls;Architecture;Autistic Disorder;Biology;Brain;Cells;Disease;Disease Susceptibility;Endocytosis;Gene Expression Profiling;Gene Regulatory Networks;Genes;Genetic Predisposition to Disease;Genetics;Humans;Hypothalamus;Mental Disorders;Mutation;Neurons;Nucleus Accumbens;Oxytocin;Protein Isoforms;RNA, Long Noncoding;Risk;Schizophrenia;Sequence Determinations, RNA;Transcriptome		Hartl, Christopher L;Ramaswami, Gokul;Pembroke, William G;Muller, Sandrine;Pintacuda, Greta;Saha, Ashis;Parsana, Princy;Battle, Alexis;Lage, Kasper;Geschwind, Daniel H	[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[David Geffen School of Medicine, University of California, Los Angeles];[Broad Institute of MIT and Harvard, Massachusetts General Hospital];[Broad Institute of MIT and Harvard, Harvard University];[Johns Hopkins University];[Johns Hopkins University];[Johns Hopkins University];[Broad Institute of MIT and Harvard, Massachusetts General Hospital, University of Copenhagen];[David Geffen School of Medicine, University of California, Los Angeles]		4	Nature neuroscience	24	9	1313-1323
U01MH115747	Group 6	Imaging								10.1016/j.jsb.2018.07.007	30017701	2018	A simple and robust procedure for preparing graphene-oxide cryo-EM grids.	Graphene oxide (GO) sheets have been used successfully as a supporting substrate film in several recent cryogenic electron-microscopy (cryo-EM) studies of challenging biological macromolecules. However, difficulties in preparing GO-covered holey carbon EM grids have limited their widespread use. Here, we report a simple and robust method for covering holey carbon EM grids with GO sheets and demonstrate that these grids can be used for high-resolution single particle cryo-EM. GO substrates adhere macromolecules, allowing cryo-EM grid preparation with lower specimen concentrations and provide partial protection from the air-water interface. Additionally, the signal of the GO lattice beneath the frozen-hydrated specimen can be discerned in many motion-corrected micrographs, providing a high-resolution fiducial for evaluating beam-induced motion correction.	Cryoelectron Microscopy;Graphite;Oxides;Specimen Handling	Air;Biopharmaceuticals;Carbon;Cryoelectron Microscopy;Films as Topic;Graphene;Graphite;Methods;Microscopy, Electron;Motion;Oxides;Procedures;Report;Specimen Handling;Water	Cryo-EM;EM grids;Graphene-oxide;Motion correction	Palovcak, Eugene;Wang, Feng;Zheng, Shawn Q;Yu, Zanlin;Li, Sam;Betegon, Miguel;Bulkley, David;Agard, David A;Cheng, Yifan	[University of California, San Francisco];[University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco]	2.35	44	Journal of structural biology	204	1	80-84
U01MH115747	Group 6									10.1016/j.neuron.2018.10.015	30359605	2018	Lost in Translation: Traversing the Complex Path from Genomics to Therapeutics in Autism Spectrum Disorder.	Recent progress in the genomics of non-syndromic autism spectrum disorder (nsASD) highlights rare, large-effect, germline, heterozygous de novo coding mutations. This distinguishes nsASD from later-onset psychiatric disorders where gene discovery efforts have predominantly yielded common alleles of small effect. These differences point to distinctive opportunities for clarifying the neurobiology of nsASD and developing novel treatments. We argue that the path ahead also presents key challenges, including distinguishing human pathophysiology from the potentially pleiotropic neurobiology mediated by established risk genes. We present our view of some of the conceptual limitations of traditional studies of model organisms, suggest a strategy focused on investigating the convergence of multiple nsASD genes, and propose that the detailed characterization of the molecular and cellular landscapes of developing human brain is essential to illuminate disease mechanisms. Finally, we address how recent advances are leading to novel strategies for therapeutics that target various points along the path from genes to behavior.	Autism Spectrum Disorder;Brain;Genetic Therapy;Genomics;Humans;Mutation	Address;Alleles;Autism Spectrum Disorder;Behavior;Brain;Candidate Gene Identification;Coding;Disease;Gene Therapy;Genes;Genetic Therapy;Genomics;Humans;Mental Disorders;Mutation;Neurobiology;Neurodevelopmental Disorders;Neurosciences;Risk;Therapeutics;Translations	autism spectrum disorder;convergence;convergence neuroscience;de novo mutation;gene therapy;genomics;human brain development;neurodevelopmental disorders;non-syndromic autism spectrum disorder;transcriptomics	Sestan, Nenad;State, Matthew W	[Yale Child Study Center, Yale School of Medicine, Yale University];[Quantitative Biosciences Institute, University of California, San Francisco]	3.06	53	Neuron	100	2	406-423
U01MH115747	Group 6	Proteomics			NDEx::f93f402c-86d4-11e7-a10d-0ac135e8bacf, 08ba2a31-86da-11e7-a10d-0ac135e8bacf, 18dc9109-86da-11e7-a10d-0ac135e8bacf					10.1016/j.isci.2019.05.025	31174177	2019	A Fast and Flexible Framework for Network-Assisted Genomic Association.	We present an accessible, fast, and customizable network propagation system for pathway boosting and interpretation of genome-wide association studies. This system-NAGA (Network Assisted Genomic Association)-taps the NDEx biological network resource to gain access to thousands of protein networks and select those most relevant and performative for a specific association study. The method works efficiently, completing genome-wide analysis in under 5 minutes on a modern laptop computer. We show that NAGA recovers many known disease genes from analysis of schizophrenia genetic data, and it substantially boosts associations with previously unappreciated genes such as amyloid beta precursor. On this and seven other gene-disease association tasks, NAGA outperforms conventional approaches in recovery of known disease genes and replicability of results. Protein interactions associated with disease are visualized and annotated in Cytoscape, which, in addition to standard programmatic interfaces, allows for downstream analysis.		Amyloid beta-Peptides;Association;Bio-Informatics;Biological Science Disciplines;Biopharmaceuticals;Computers;Disease;Genes;Genetics;Genome;Genome-Wide Association Study;Genomics;Methods;Proteins;Resources;Schizophrenia;Standards;Work	Bioinformatics;Biological Sciences;Genomics	Carlin, Daniel E;Fong, Samson H;Qin, Yue;Jia, Tongqiu;Huang, Justin K;Bao, Bokan;Zhang, Chao;Ideker, Trey	[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego]	0.53	8	iScience	16		155-161
U01MH115747	Group 6									10.1016/j.cell.2019.07.046	31474367	2019	Anti-CRISPR-Associated Proteins Are Crucial Repressors of Anti-CRISPR Transcription.	Phages express anti-CRISPR (Acr) proteins to inhibit CRISPR-Cas systems that would otherwise destroy their genomes. Most acr genes are located adjacent to anti-CRISPR-associated (aca) genes, which encode proteins with a helix-turn-helix DNA-binding motif. The conservation of aca genes has served as a signpost for the identification of acr genes, but the function of the proteins encoded by these genes has not been investigated. Here we reveal that an acr-associated promoter drives high levels of acr transcription immediately after phage DNA injection and that Aca proteins subsequently repress this transcription. Without Aca activity, this strong transcription is lethal to a phage. Our results demonstrate how sufficient levels of Acr proteins accumulate early in the infection process to inhibit existing CRISPR-Cas complexes in the host cell. They also imply that the conserved role of Aca proteins is to mitigate the deleterious effects of strong constitutive transcription from acr promoters.	Bacteriophages;CRISPR-Associated Proteins;CRISPR-Cas Systems;Clustered Regularly Interspaced Short Palindromic Repeats;Escherichia coli;Promoter Regions, Genetic;Pseudomonas aeruginosa;Transcription Factors;Transcription, Genetic;Viral Proteins	Bacteriophages;CRISPR-Associated Proteins;CRISPR-Cas Systems;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;DNA;Drive;Escherichia coli;Gene Transfer, Horizontal;Genes;Genome;Infections;Injections;Promoter Regions, Genetic;Proteins;Pseudomonas aeruginosa;Role;Transcription Factors;Transcription, Genetic;Viral Proteins	CRISPR-Cas;Horizontal gene transfer;Phage;Pseudomonas aeruginosa;Transcriptional regulator;anti-CRISPR	Stanley, Sabrina Y;Borges, Adair L;Chen, Kuei-Ho;Swaney, Danielle L;Krogan, Nevan J;Bondy-Denomy, Joseph;Davidson, Alan R	[University of Toronto];[University of California, San Francisco];[Gladstone Institutes];[Gladstone Institutes, Quantitative Biosciences Institute, University of California, San Francisco];[Gladstone Institutes, Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco];[University of Toronto]	3.60	46	Cell	178	6	1452-1464.e13
U01MH115747	Group 6									10.1038/s42003-019-0411-9	31069265	2019	Automated four-dimensional long term imaging enables single cell tracking within organotypic brain slices to study neurodevelopment and degeneration.	Current approaches for dynamic profiling of single cells rely on dissociated cultures, which lack important biological features existing in tissues. Organotypic slice cultures preserve aspects of structural and synaptic organisation within the brain and are amenable to microscopy, but established techniques are not well adapted for high throughput or longitudinal single cell analysis. Here we developed a custom-built, automated confocal imaging platform, with improved organotypic slice culture and maintenance. The approach enables fully automated image acquisition and four-dimensional tracking of morphological changes within individual cells in organotypic cultures from rodent and human primary tissues for at least 3 weeks. To validate this system, we analysed neurons expressing a disease-associated version of huntingtin (HTT586Q138-EGFP), and observed that they displayed hallmarks of Huntington's disease and died sooner than controls. By facilitating longitudinal single-cell analyses of neuronal physiology, our system bridges scales necessary to attain statistical power to detect developmental and disease phenotypes.	Amino Acid Substitution;Animals;Animals, Newborn;Cell Differentiation;Cell Tracking;Gene Expression;Hippocampus;Humans;Huntingtin Protein;Huntington Disease;Mice;Mice, Inbred C57BL;Microscopy, Confocal;Models, Biological;Neural Stem Cells;Neurons;Primary Cell Culture;Single-Cell Analysis;Tissue Culture Techniques	Amino Acid Substitution;Animals;Animals, Newborn;Biopharmaceuticals;Brain;Cell Differentiation;Cell Tracking;Cells;Culture;Customs;Disease;Disease Models, Animal;Gene Expression;Hippocampus;Humans;Huntingtin Protein;Huntington Disease;Maintenance;Mice;Mice, Inbred C57BL;Microscopy;Microscopy, Confocal;Models, Biological;Neural Stem Cells;Neurons;Organizations;Phenotype;Physiology;Power, Psychological;Primary Cell Culture;Rodentia;Scales;Single-Cell Analysis;Time-Lapse Imaging;Tissue Culture Techniques;Tissues	Animal disease models;Confocal microscopy;Neurodegeneration;Time-lapse imaging;Tissue culture	Linsley, Jeremy W;Tripathi, Atmiyata;Epstein, Irina;Schmunk, Galina;Mount, Elliot;Campioni, Matthew;Oza, Viral;Barch, Mariya;Javaherian, Ashkan;Nowakowski, Tomasz J;Samsi, Siddharth;Finkbeiner, Steven	;;;[University of California, San Francisco];;;;;;[University of California, San Francisco];[Luxembourg Center for Systems Biomedicine, MIT Lincoln Laboratory, University of Luxembourg];[Gladstone Institutes, University of California, San Francisco]	0.89	12	Communications biology	2		155
U01MH115747	Group 6									10.1038/s41436-019-0576-0	31263215	2019	DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract.	Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a's role in renal development. Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA. Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.	Adolescent;Adult;Animals;Child;Child, Preschool;Databases, Genetic;Disease Models, Animal;Exome;Female;Haploinsufficiency;Humans;Intellectual Disability;Kidney;Male;Nephrons;Protein Serine-Threonine Kinases;Protein-Tyrosine Kinases;Urinary Tract;Urogenital Abnormalities;Whole Exome Sequencing;Xenopus laevis;Young Adult	Adolescent;Adult;Animals;Child;Child, Preschool;Database;Databases, Genetic;Disease Models, Animal;Embryo;Exome;Female;Genitalia;Goals;Haploinsufficiency;Humans;Intellectual Disability;Kidney;Male;Nephrons;Observation;Paper;Patients;Phenotype;Protein-Serine-Threonine Kinases;Protein-Tyrosine Kinases;RNA;Role;Screening;Syndrome;Urinary Tract;Urogenital Abnormalities;Whole Exome Sequencing;Xenopus;Xenopus laevis;Young Adult	CAKUT;DYRK1A;Xenopus;exome sequencing;kidney	Blackburn, Alexandria T M;Bekheirnia, Nasim;Uma, Vanessa C;Corkins, Mark E;Xu, Yuxiao;Rosenfeld, Jill A;Bainbridge, Matthew N;Yang, Yaping;Liu, Pengfei;Madan-Khetarpal, Suneeta;Delgado, Mauricio R;Hudgins, Louanne;Krantz, Ian;Rodriguez-Buritica, David;Wheeler, Patricia G;Al-Gazali, Lihadh;Mohamed Saeed Mohamed Al Shamsi, Aisha;Gomez-Ospina, Natalia;Chao, Hsiao-Tuan;Mirzaa, Ghayda M;Scheuerle, Angela E;Kukolich, Mary K;Scaglia, Fernando;Eng, Christine;Willsey, Helen Rankin;Braun, Michael C;Lamb, Dolores J;Miller, Rachel K;Bekheirnia, Mir Reza	[McGovern Medical School, The University of Texas MD Anderson Cancer Center, University of Texas Health Science Center at Houston];[Baylor College of Medicine, Texas Children's Cancer Center];[Baylor College of Medicine];[McGovern Medical School, University of Texas Health Science Center at Houston];[University of California, Berkeley, University of California, San Francisco];[Baylor College of Medicine];[Codified Genomics, LLC, Rady Children's Institute for Genomic Medicine];[Baylor College of Medicine];[Baylor College of Medicine];[Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine];[UT Southwestern Medical Center];[Stanford University];[Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania];[McGovern Medical School, University of Texas School of Public Health];;[United Arab Emirates University];[Tawam Hospital];[Stanford University];[Baylor College of Medicine, Texas Children's Cancer Center];[Center for Integrative Brain Research Seattle, Children's National Medical Center, University of Washington];[UT Southwestern Medical Center];[Cook Children's Medical Center];[Baylor College of Medicine, Prince of Wales Hospital, Texas Children's Cancer Center];[Baylor College of Medicine];[University of California, Berkeley, University of California, San Francisco];[Baylor College of Medicine, Texas Children's Cancer Center];[Weill Cornell Medicine];[McGovern Medical School, The University of Texas MD Anderson Cancer Center, University of Texas Health Science Center at Houston];[Baylor College of Medicine, Texas Children's Cancer Center]	0.83	11	Genetics in medicine : official journal of the American College of Medical Genetics	21	12	2755-2764
U01MH115747	Group 6									10.1016/j.brainres.2019.146470	31542572	2019	Human brain development through the lens of cerebral organoid models.	The brain is one of the most complex organs in the body, which emerges from a relatively simple set of basic 'building blocks' during early development according to complex cellular and molecular events orchestrated through a set of inherited instructions. Innovations in stem cell technologies have enabled modelling of neural cells using two- and three-dimensional cultures. In particular, cerebral ('brain') organoids have taken the center stage of brain development models that have the potential for providing meaningful insight into human neurodevelopmental and neurological disorders. We review the current understanding of cellular events during human brain organogenesis, and the events occurring during cerebral organoid differentiation. We highlight the strengths and weaknesses of this experimental model system. In particular, we explain evidence that organoids can mimic many aspects of early neural development, including neural induction, patterning, and broad neurogenesis and gliogenesis programs, offering the opportunity to study genetic regulation of these processes in a human context. Several shortcomings of the current culture methods limit the utility of cerebral organoids to spontaneously give rise to many important cell types, and to model higher order features of tissue organization. We suggest that future studies aim to improve these features in order to make them better models for the study of laminar organization, circuit formation and how disruptions of these processes relate to disease.	Animals;Brain;Cell Differentiation;Humans;Induced Pluripotent Stem Cells;Models, Neurological;Neurogenesis;Neurons;Organogenesis;Organoids	Animals;Brain;Cell Differentiation;Cells;Comprehension;Culture;Disease;Experimental Model;Future;Genetics;Humans;Induced Pluripotent Stem Cells;Instruction;Methods;Models, Neurological;Nervous System Diseases;Neurogenesis;Neurons;Organizations;Organogenesis;Organoids;Program;Regulation;Review;Stem Cells;Technology;Tissues	Brain organoids;Neural development	Andrews, Madeline G;Nowakowski, Tomasz J	[University of California, San Francisco];[BioHub, University of California, San Francisco]	0.78	12	Brain research	1725		146470
U01MH115747	Group 6									10.1016/j.gde.2019.04.005	31288129	2019	Mapping the protein-protein and genetic interactions of cancer to guide precision medicine.	Massive efforts to sequence cancer genomes have compiled an impressive catalogue of cancer mutations, revealing the recurrent exploitation of a handful of 'hallmark cancer pathways'. However, unraveling how sets of mutated proteins in these and other pathways hijack pro-proliferative signaling networks and dictate therapeutic responsiveness remains challenging. Here, we show that cancer driver protein-protein interactions are enriched for additional cancer drivers, highlighting the power of physical interaction maps to explain known, as well as uncover new, disease-promoting pathway interrelationships. We hypothesize that by systematically mapping the protein-protein and genetic interactions in cancer-thereby creating Cancer Cell Maps-we will create resources against which to contextualize a patient's mutations into perturbed pathways/complexes and thereby specify a matching targeted therapeutic cocktail.	Computational Biology;Databases, Genetic;Epistasis, Genetic;Gene Regulatory Networks;Humans;Mutation;Neoplasms;Precision Medicine;Protein Interaction Maps;Signal Transduction	Cancer;Catalog;Cells;Computational Biology;Databases, Genetic;Disease;Epistasis, Genetic;Gene Regulatory Networks;Genetics;Genome;Humans;Map;Mutation;Neoplasms;News;Patients;Power, Psychological;Precision Medicine;Protein Interaction Maps;Proteins;Resources;Signal Transduction;Therapeutics		Bouhaddou, Mehdi;Eckhardt, Manon;Chi Naing, Zun Zar;Kim, Minkyu;Ideker, Trey;Krogan, Nevan J	[Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco];[University of California, San Diego];[Quantitative Biosciences Institute, University of California, San Francisco]	0.69	11	Current opinion in genetics & development	54		110-117
U01MH115747	Group 6	Review								10.1371/journal.pgen.1008519	31770365	2019	The great hairball gambit.		Genetic Loci;Genetic Predisposition to Disease;Genome-Wide Association Study;Humans;Metabolic Networks and Pathways;Protein Interaction Maps	Genetic Loci;Genetic Predisposition to Disease;Genome-Wide Association Study;Humans;Metabolic Networks and Pathways;Protein Interaction Maps		Flint, Jonathan;Ideker, Trey	[University of California, Los Angeles];[University of California, San Diego]	0.61	11	PLoS genetics	15	11	e1008519
U01MH115747	Group 6									10.1016/j.jsb.2019.107437	31866389	2020	Amino and PEG-amino graphene oxide grids enrich and protect samples for high-resolution single particle cryo-electron microscopy.	Cryo-EM samples prepared using traditional methods often suffer from too few particles, poor particle distribution, strongly biased orientation, or damage from the air-water interface. Here we report that functionalization of graphene oxide (GO) coated grids with amino groups concentrates samples on the grid with improved distribution and orientation. By introducing a PEG spacer, particles are kept away from both the GO surface and the air-water interface, protecting them from potential denaturation.	Amines;Cryoelectron Microscopy;Graphite;Polyethylene Glycols;Single Molecule Imaging;Water	Air;Amines;Cryoelectron Microscopy;Graphene;Graphite;Methods;Orientation;Oxides;Polyethylene Glycols;Report;Single Molecule Imaging;Water	Air-water interface;Amino functionalization;Cryo-EM;Graphene oxide;Sample preparation	Wang, Feng;Yu, Zanlin;Betegon, Miguel;Campbell, Melody G;Aksel, Tural;Zhao, Jianhua;Li, Sam;Douglas, Shawn M;Cheng, Yifan;Agard, David A	[Howard Hughes Medical Institute, University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco];[University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco];[University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco]	1.56	11	Journal of structural biology	209	2	107437
U01MH115747	Group 6									10.1038/s41572-019-0138-4	31949163	2020	Autism spectrum disorder.	Autism spectrum disorder is a construct used to describe individuals with a specific combination of impairments in social communication and repetitive behaviours, highly restricted interests and/or sensory behaviours beginning early in life. The worldwide prevalence of autism is just under 1%, but estimates are higher in high-income countries. Although gross brain pathology is not characteristic of autism, subtle anatomical and functional differences have been observed in post-mortem, neuroimaging and electrophysiological studies. Initially, it was hoped that accurate measurement of behavioural phenotypes would lead to specific genetic subtypes, but genetic findings have mainly applied to heterogeneous groups that are not specific to autism. Psychosocial interventions in children can improve specific behaviours, such as joint attention, language and social engagement, that may affect further development and could reduce symptom severity. However, further research is necessary to identify the long-term needs of people with autism, and treatments and the mechanisms behind them that could result in improved independence and quality of life over time. Families are often the major source of support for people with autism throughout much of life and need to be considered, along with the perspectives of autistic individuals, in both research and practice.	Autism Spectrum Disorder;Humans;Quality of Life;Sex Characteristics	Affect;Attention;Autism Spectrum Disorder;Autistic Disorder;Behavior;Brain;Child;Family;Genetics;Humans;Income;Joints;Language;Lead;Life;Needs;Neuroimaging;Pathology;Persons;Phenotype;Prevalence;Psychosocial Intervention;Quality of Life;Research;Sex Characteristics;Social Communication;Social Engagement;Therapeutics;Time		Lord, Catherine;Brugha, Traolach S;Charman, Tony;Cusack, James;Dumas, Guillaume;Frazier, Thomas;Jones, Emily J H;Jones, Rebecca M;Pickles, Andrew;State, Matthew W;Taylor, Julie Lounds;Veenstra-VanderWeele, Jeremy	[University of California, Los Angeles];[University of Leicester];[Institute of Psychiatry, Psychology and Neuroscience, King's College London];[Autistica (UK)];[National Center for Scientific Research (France), Pasteur Institute, University of Paris];[Autism Speaks];[University of London];;[Institute of Psychiatry, Psychology and Neuroscience, King's College London];[University of California, San Francisco];[Vanderbilt University Medical Center];[Columbia University]	34.24	193	Nature reviews. Disease primers	6	1	5
U01MH115747	Group 6	Genomics								10.1038/s41582-020-0373-z	32641861	2020	CRISPR-based functional genomics for neurological disease.	Neurodegenerative, neurodevelopmental and neuropsychiatric disorders are among the greatest public health challenges, as many lack disease-modifying treatments. A major reason for the absence of effective therapies is our limited understanding of the causative molecular and cellular mechanisms. Genome-wide association studies are providing a growing catalogue of disease-associated genetic variants, and the next challenge is to elucidate how these variants cause disease and to translate this understanding into therapies. This Review describes how new CRISPR-based functional genomics approaches can uncover disease mechanisms and therapeutic targets in neurological diseases. The bacterial CRISPR system can be used in experimental disease models to edit genomes and to control gene expression levels through CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa). These genetic perturbations can be implemented in massively parallel genetic screens to evaluate the functional consequences for human cells. CRISPR screens are particularly powerful in combination with induced pluripotent stem cell technology, which enables the derivation of differentiated cell types, such as neurons and glia, and brain organoids from cells obtained from patients. Modelling of disease-associated changes in gene expression via CRISPRi and CRISPRa can pinpoint causal changes. In addition, genetic modifier screens can be used to elucidate disease mechanisms and causal determinants of cell type-selective vulnerability and to identify therapeutic targets.	Animals;CRISPR-Cas Systems;Gene Editing;Genome-Wide Association Study;Genomics;Humans;Induced Pluripotent Stem Cells;Nervous System Diseases	Animals;Brain;CRISPR-Cas Systems;Catalog;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Comprehension;Disease;Gene Editing;Gene Expression;Genetics;Genome;Genome-Wide Association Study;Genomics;Humans;Induced Pluripotent Stem Cells;Nervous System Diseases;Neuroglia;Neurons;News;Organoids;Patients;Public Health;Review;Technology;Therapeutics		Kampmann, Martin	BioHub;University of California, San Francisco	3.08	30	Nature reviews. Neurology	16	9	465-480
U01MH115747	Group 6									10.1016/j.nbd.2020.105088	32977020	2020	Functional genomics, genetic risk profiling and cell phenotypes in neurodegenerative disease.	Human genetics provides unbiased insights into the causes of human disease, which can be used to create a foundation for effective ways to more accurately diagnose patients, stratify patients for more successful clinical trials, discover and develop new therapies, and ultimately help patients choose the safest and most promising therapeutic option based on their risk profile. But the process for translating basic observations from human genetics studies into pathogenic disease mechanisms and treatments is laborious and complex, and this challenge has particularly slowed the development of interventions for neurodegenerative disease. In this review, we discuss the many steps in the process, the important considerations at each stage, and some of the latest tools and technologies that are available to help investigators translate insights from human genetics into diagnostic and therapeutic strategies that will lead to the sort of advances in clinical care that make a difference for patients.	Cell Differentiation;Genetic Diseases, Inborn;Genomics;Humans;Neurodegenerative Diseases;Phenotype;Risk	Cell Differentiation;Cells;Clinical Trial;Diagnosis;Disease;Foundations;Genetic Diseases, Inborn;Genetics;Genomics;Human Genetics;Humans;Lead;Neurodegenerative Diseases;News;Observation;Patients;Phenotype;Research Personnel;Review;Risk;Technology;Therapeutics;Translating		Finkbeiner, Steven	Gladstone Institutes	0.00	0	Neurobiology of disease	146		105088
U01MH115747	Group 6	Review								10.1073/pnas.2009707117	32913054	2020	General and robust covalently linked graphene oxide affinity grids for high-resolution cryo-EM.	Affinity grids have great potential to facilitate rapid preparation of even quite impure samples in single-particle cryo-electron microscopy (EM). Yet despite the promising advances of affinity grids over the past decades, no single strategy has demonstrated general utility. Here we chemically functionalize cryo-EM grids coated with mostly one or two layers of graphene oxide to facilitate affinity capture. The protein of interest is tagged using a system that rapidly forms a highly specific covalent bond to its cognate catcher linked to the grid via a polyethylene glycol (PEG) spacer. Importantly, the spacer keeps particles away from both the air-water interface and the graphene oxide surface, protecting them from potential denaturation and rendering them sufficiently flexible to avoid preferential sample orientation concerns. Furthermore, the PEG spacer successfully reduces nonspecific binding, enabling high-resolution reconstructions from a much cruder lysate sample.	Cryoelectron Microscopy;Graphite;Polyethylene Glycols;Specimen Handling	Air;Cryoelectron Microscopy;Form;Graphene;Graphite;Orientation;Oxides;Polyethylene Glycols;Proteins;Specimen Handling;Water	affinity grid;cryo-EM;graphene oxide;single-particle reconstruction	Wang, Feng;Liu, Yanxin;Yu, Zanlin;Li, Sam;Feng, Shengjie;Cheng, Yifan;Agard, David A	[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[Howard Hughes Medical Institute, University of California, San Francisco];[University of California, San Francisco]	2.43	20	Proceedings of the National Academy of Sciences of the United States of America	117	39	24269-24273
U01MH115747	Group 6					GSE149538				10.1242/dev.189290	32467234	2020	The neurodevelopmental disorder risk gene DYRK1A is required for ciliogenesis and control of brain size in Xenopus embryos.	DYRK1A [dual specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A] is a high-confidence autism risk gene that encodes a conserved kinase. In addition to autism, individuals with putative loss-of-function variants in DYRK1A exhibit microcephaly, intellectual disability, developmental delay and/or congenital anomalies of the kidney and urinary tract. DYRK1A is also located within the critical region for Down syndrome; therefore, understanding the role of DYRK1A in brain development is crucial for understanding the pathobiology of multiple developmental disorders. To characterize the function of this gene, we used the diploid frog Xenopus tropicalis We discover that Dyrk1a is expressed in ciliated tissues, localizes to ciliary axonemes and basal bodies, and is required for ciliogenesis. We also demonstrate that Dyrk1a localizes to mitotic spindles and that its inhibition leads to decreased forebrain size, abnormal cell cycle progression and cell death during brain development. These findings provide hypotheses about potential mechanisms of pathobiology and underscore the utility of X. tropicalis as a model system for understanding neurodevelopmental disorders.	Animals;Brain;Cell Cycle;Cell Survival;Cilia;Embryo, Nonmammalian;Gene Expression Regulation, Developmental;Genetic Predisposition to Disease;Neurodevelopmental Disorders;Organ Size;Organogenesis;Phenotype;Protein Serine-Threonine Kinases;Protein-Tyrosine Kinases;Risk Factors;Spindle Apparatus;Telencephalon;Xenopus;Xenopus Proteins	Animals;Autistic Disorder;Axoneme;Basal Bodies;Brain;Cell Cycle;Cell Death;Cell Survival;Cilia;Comprehension;Diploidy;Down Syndrome;Embryo;Embryo, Nonmammalian;Exhibition;Gene Expression Regulation, Developmental;Genes;Genetic Predisposition to Disease;Intellectual Disability;Kidney;Lead;Microcephaly;Microtubules;Mitotic Spindle Apparatus;Neurodevelopmental Disorders;Organ Size;Organogenesis;Phenotype;Phosphorylation;Phosphotransferases;Prosencephalon;Protein-Serine-Threonine Kinases;Protein-Tyrosine Kinases;Risk;Risk Factors;Role;Specificity;Spindle Apparatus;Telencephalon;Tissues;Tyrosine;Urinary Tract;Xenopus;Xenopus Proteins	Autism;Ciliogenesis;DYRK1A;Down Syndrome;Microtubules;Spindle	Willsey, Helen Rankin;Xu, Yuxiao;Everitt, Amanda;Dea, Jeanselle;Exner, Cameron R T;Willsey, A Jeremy;State, Matthew W;Harland, Richard M	[Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, Berkeley, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, Berkeley, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, Berkeley, University of California, San Francisco]	1.48	12	Development (Cambridge, England)	147	21
U01MH115747	Group 6	Proteomics			NDEx::cedacca2-8f2c-11ea-aaef-0ac135e8bacf,NDEx::5109757e-a5d6-11ea-aaef-0ac135e8bacf					10.1016/j.cels.2021.07.009	34411509	2021	A convergent molecular network underlying autism and congenital heart disease.	Patients with neurodevelopmental disorders, including autism, have an elevated incidence of congenital heart disease, but the extent to which these conditions share molecular mechanisms remains unknown. Here, we use network genetics to identify a convergent molecular network underlying autism and congenital heart disease. This network is impacted by damaging genetic variants from both disorders in multiple independent cohorts of patients, pinpointing 101 genes with shared genetic risk. Network analysis also implicates risk genes for each disorder separately, including 27 previously unidentified genes for autism and 46 for congenital heart disease. For 7 genes with shared risk, we create engineered disruptions in Xenopus tropicalis, confirming both heart and brain developmental abnormalities. The network includes a family of ion channels, such as the sodium transporter SCN2A, linking these functions to early heart and brain development. This study provides a road map for identifying risk genes and pathways involved in co-morbid conditions.	Autism Spectrum Disorder;Autistic Disorder;Heart Defects, Congenital;Humans	Autism Spectrum Disorder;Autistic Disorder;Brain;Family;Genes;Genetics;Heart;Heart Defects, Congenital;Humans;Incidence;Ion Channels;Map;Neurodevelopmental Disorders;Patients;Risk;Sodium;Systems Biology;Xenopus	Subject areas: systems biology;autism;congenital heart disease;network genetics	Rosenthal, Sara Brin;Willsey, Helen Rankin;Xu, Yuxiao;Mei, Yuan;Dea, Jeanselle;Wang, Sheng;Curtis, Charlotte;Sempou, Emily;Khokha, Mustafa K;Chi, Neil C;Willsey, Arthur Jeremy;Fisch, Kathleen M;Ideker, Trey	[University of California, San Diego];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Diego];[University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco];[University of California, San Diego];[Yale School of Medicine];[Yale School of Medicine];[University of California, San Diego];[Quantitative Biosciences Institute, University of California, San Francisco];[University of California, San Diego];[University of California, San Diego]		3	Cell systems	12	11	1094-1107.e6
U01MH115747	Group 6	Genomics				GSE171553				10.1038/s41586-021-04115-9	34819669	2021	A multi-scale map of cell structure fusing protein images and interactions.	The cell is a multi-scale structure with modular organization across at least four orders of magnitude1. Two central approaches for mapping this structure-protein fluorescent imaging and protein biophysical association-each generate extensive datasets, but of distinct qualities and resolutions that are typically treated separately2,3. Here we integrate immunofluorescence images in the Human Protein Atlas4 with affinity purifications in BioPlex5 to create a unified hierarchical map of human cell architecture. Integration is achieved by configuring each approach as a general measure of protein distance, then calibrating the two measures using machine learning. The map, known as the multi-scale integrated cell (MuSIC 1.0), resolves 69 subcellular systems, of which approximately half are to our knowledge undocumented. Accordingly, we perform 134 additional affinity purifications and validate subunit associations for the majority of systems. The map reveals a pre-ribosomal RNA processing assembly and accessory factors, which we show govern rRNA maturation, and functional roles for SRRM1 and FAM120C in chromatin and RPS3A in splicing. By integration across scales, MuSIC increases the resolution of imaging while giving protein interactions a spatial dimension, paving the way to incorporate diverse types of data in proteome-wide cell maps.	Antigens, Nuclear;Chromatin;Chromosomes;Humans;Nuclear Matrix-Associated Proteins;Proteome;RNA, Ribosomal;RNA-Binding Proteins	Antigens, Nuclear;Architecture;Association;Atlas;Cells;Chromatin;Chromosomes;Dataset;Humans;Immunofluorescence;Knowledge;Machine Learning;Map;Measures;Nuclear Matrix-Associated Proteins;Organizations;Proteins;Proteome;RNA;RNA, Ribosomal;RNA-Binding Proteins;Role;Scales		Qin, Yue;Huttlin, Edward L;Winsnes, Casper F;Gosztyla, Maya L;Wacheul, Ludivine;Kelly, Marcus R;Blue, Steven M;Zheng, Fan;Chen, Michael;Schaffer, Leah V;Licon, Katherine;Bäckström, Anna;Vaites, Laura Pontano;Lee, John J;Ouyang, Wei;Liu, Sophie N;Zhang, Tian;Silva, Erica;Park, Jisoo;Pitea, Adriana;Kreisberg, Jason F;Gygi, Steven P;Ma, Jianzhu;Harper, J Wade;Yeo, Gene W;Lafontaine, Denis L J;Lundberg, Emma;Ideker, Trey	[University of California, San Diego];[Harvard Medical School];[KTH Royal Institute of Technology];[University of California, San Diego];[Fonds de la Recherche Scientifique, Université Libre de Bruxelles];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[KTH Royal Institute of Technology];[Harvard Medical School];[University of California, San Diego];[KTH Royal Institute of Technology];[University of California, San Diego];[Harvard Medical School];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[University of California, San Diego];[Harvard Medical School];[Peking University];[Harvard Medical School];[University of California, San Diego];[Fonds de la Recherche Scientifique, Université Libre de Bruxelles];[BioHub, KTH Royal Institute of Technology, Stanford University];[University of California, San Diego]	1.19	5	Nature	600	7889	536-542
U01MH115747	Group 6									10.1016/j.cell.2021.02.022	33765441	2021	Creating collaboration by breaking down scientific barriers.	The scientific world rewards the individual while often discouraging collaboration. However, times of crisis show us how much more we can accomplish when we work together. Here, we describe our approach to breaking down silos and fostering global collaborations and share the lessons we have learned, especially pertaining to research on SARS-CoV-2.	COVID-19;Communication;Cooperative Behavior;Humans;Internationality;Research Support as Topic;SARS-CoV-2;Science	COVID-19;Communication;Cooperative Behavior;Fostering;Humans;Internationality;Research;Research Support as Topic;Reward;SARS-CoV-2;Science;Time;Work		Fabius, Jacqueline M;Krogan, Nevan J	[Quantitative Biosciences Institute, University of California, San Francisco];[Gladstone Institutes, Icahn School of Medicine, Quantitative Biosciences Institute, University of California, San Francisco]		3	Cell	184	9	2271-2275
U01MH115747	Group 6	Imaging								10.1242/dev.199664	34739029	2021	Deep learning is widely applicable to phenotyping embryonic development and disease.	Genome editing simplifies the generation of new animal models for congenital disorders. However, the detailed and unbiased phenotypic assessment of altered embryonic development remains a challenge. Here, we explore how deep learning (U-Net) can automate segmentation tasks in various imaging modalities, and we quantify phenotypes of altered renal, neural and craniofacial development in Xenopus embryos in comparison with normal variability. We demonstrate the utility of this approach in embryos with polycystic kidneys (pkd1 and pkd2) and craniofacial dysmorphia (six1). We highlight how in toto light-sheet microscopy facilitates accurate reconstruction of brain and craniofacial structures within X. tropicalis embryos upon dyrk1a and six1 loss of function or treatment with retinoic acid inhibitors. These tools increase the sensitivity and throughput of evaluating developmental malformations caused by chemical or genetic disruption. Furthermore, we provide a library of pre-trained networks and detailed instructions for applying deep learning to the reader's own datasets. We demonstrate the versatility, precision and scalability of deep neural network phenotyping on embryonic disease models. By combining light-sheet microscopy and deep learning, we provide a framework for higher-throughput characterization of embryonic model organisms. This article has an associated 'The people behind the papers' interview.	Animals;Craniofacial Abnormalities;Deep Learning;Disease Models, Animal;Embryonic Development;Image Processing, Computer-Assisted;Mice;Microscopy;Mutation;Neural Networks, Computer;Neurodevelopmental Disorders;Phenotype;Polycystic Kidney Diseases;Xenopus Proteins;Xenopus laevis	Animals;Brain;Congenital Disorders;Craniofacial Abnormalities;Dataset;Deep Learning;Disease;Disease Models, Animal;Embryo;Embryonic Development;Generations;Genetics;Genome Editing;Image Processing, Computer-Assisted;Instruction;Interview;Kidney Diseases, Cystic;Kidney, Polycystic;Libraries;Light;Mice;Microscopy;Models, Animal;Mutation;Neural Networks, Computer;Neurodevelopmental Disorders;News;Paper;Persons;Phenotype;Polycystic Kidney Diseases;Sensitivity;Therapeutics;Tretinoin;Xenopus;Xenopus Proteins;Xenopus laevis	           Xenopus         ;Craniofacial dysmorphia;Cystic kidney disease;Deep learning;Light-sheet microscopy;U-Net	Naert, Thomas;Çiçek, Özgün;Ogar, Paulina;Bürgi, Max;Shaidani, Nikko-Ideen;Kaminski, Michael M;Xu, Yuxiao;Grand, Kelli;Vujanovic, Marko;Prata, Daniel;Hildebrandt, Friedhelm;Brox, Thomas;Ronneberger, Olaf;Voigt, Fabian F;Helmchen, Fritjof;Loffing, Johannes;Horb, Marko E;Willsey, Helen Rankin;Lienkamp, Soeren S	[University of Zurich];[University of Freiburg];[University of Zurich];[University of Zurich];[Marine Biological Laboratory];[Berlin Institute for Medical Systems Biology, Charité - Universitätsmedizin Berlin, Helmholtz Association of German Research Centers, Max Delbrück Center for Molecular Medicine];[University of California, San Francisco];[University of Zurich];[University of Zurich];[University of Zurich];[Boston Children's Hospital, Harvard Medical School];[University of Freiburg];[DeepMind Technologies Limited, University of Freiburg];[Brain Research Institute, University of Zurich];[Brain Research Institute, University of Zurich];[University of Zurich];[Marine Biological Laboratory];[University of California, San Francisco];[University of Zurich]		1	Development (Cambridge, England)	148	21
U01MH115747	Group 6	Imaging								10.1038/s41467-021-25549-9	34489414	2021	Genetically encoded cell-death indicators (GEDI) to detect an early irreversible commitment to neurodegeneration.	Cell death is a critical process that occurs normally in health and disease. However, its study is limited due to available technologies that only detect very late stages in the process or specific death mechanisms. Here, we report the development of a family of fluorescent biosensors called genetically encoded death indicators (GEDIs). GEDIs specifically detect an intracellular Ca2+ level that cells achieve early in the cell death process and that marks a stage at which cells are irreversibly committed to die. The time-resolved nature of a GEDI delineates a binary demarcation of cell life and death in real time, reformulating the definition of cell death. We demonstrate that GEDIs acutely and accurately report death of rodent and human neurons in vitro, and show that GEDIs enable an automated imaging platform for single cell detection of neuronal death in vivo in zebrafish larvae. With a quantitative pseudo-ratiometric signal, GEDIs facilitate high-throughput analysis of cell death in time-lapse imaging analysis, providing the necessary resolution and scale to identify early factors leading to cell death in studies of neurodegeneration.	Animals;Biosensing Techniques;Calcium;Cell Death;Cerebral Cortex;DNA-Binding Proteins;Disease Models, Animal;Embryo, Nonmammalian;Fluorescent Dyes;Gene Expression Regulation, Developmental;Genes, Reporter;Glutamic Acid;Green Fluorescent Proteins;Humans;Larva;Mice;Mice, Inbred C57BL;Neurodegenerative Diseases;Neurons;Primary Cell Culture;Rats;Rats, Long-Evans;Single-Cell Analysis;Superoxide Dismutase-1;Zebrafish;alpha-Synuclein	Animals;Biosensing Techniques;Biosensors;Calcium;Cell Death;Cells;Cerebral Cortex;DNA-Binding Proteins;Death;Disease;Disease Models, Animal;Embryo, Nonmammalian;Family;Fluorescent Dyes;Gene Expression Regulation, Developmental;Genes, Reporter;Glutamic Acid;Green Fluorescent Proteins;Health;Humans;In Vitro;Indicators;Larva;Life;Mice;Mice, Inbred C57BL;Nature;Neurodegenerative Diseases;Neurons;Primary Cell Culture;Rats;Rats, Long-Evans;Report;Rodentia;Scales;Single-Cell Analysis;Superoxide Dismutase-1;Technology;Time;Time-Lapse Imaging;Zebrafish;alpha-Synuclein		Linsley, Jeremy W;Shah, Kevan;Castello, Nicholas;Chan, Michelle;Haddad, Dominik;Doric, Zak;Wang, Shijie;Leks, Wiktoria;Mancini, Jay;Oza, Viral;Javaherian, Ashkan;Nakamura, Ken;Kokel, David;Finkbeiner, Steven	;;;;;[University of California, San Francisco];;;;;;[University of California, San Francisco];[University of California, San Francisco];[Gladstone Institutes]		1	Nature communications	12	1	5284
U01MH115747	Group 6	Review								10.15252/msb.20188792	33434350	2021	Mass spectrometry-based protein-protein interaction networks for the study of human diseases.	A better understanding of the molecular mechanisms underlying disease is key for expediting the development of novel therapeutic interventions. Disease mechanisms are often mediated by interactions between proteins. Insights into the physical rewiring of protein-protein interactions in response to mutations, pathological conditions, or pathogen infection can advance our understanding of disease etiology, progression, and pathogenesis and can lead to the identification of potential druggable targets. Advances in quantitative mass spectrometry (MS)-based approaches have allowed unbiased mapping of these disease-mediated changes in protein-protein interactions on a global scale. Here, we review MS techniques that have been instrumental for the identification of protein-protein interactions at a system-level, and we discuss the challenges associated with these methodologies as well as novel MS advancements that aim to address these challenges. An overview of examples from diverse disease contexts illustrates the potential of MS-based protein-protein interaction mapping approaches for revealing disease mechanisms, pinpointing new therapeutic targets, and eventually moving toward personalized applications.	Disease;Gene Regulatory Networks;Humans;Mass Spectrometry;Protein Interaction Mapping	Address;Comprehension;Disease;Gene Regulatory Networks;Humans;Infections;Lead;Mass Spectrometry;Mutation;News;Protein Interaction Mapping;Protein-Protein Interaction Network;Proteins;Review;Scales;Therapeutics	affinity purification;mass spectrometry;networks;protein-protein interactions;proximity labeling	Richards, Alicia L;Eckhardt, Manon;Krogan, Nevan J	[Gladstone Institutes, Quantitative Biosciences Institute, University of California, San Francisco];[Gladstone Institutes, Quantitative Biosciences Institute, University of California, San Francisco];[Gladstone Institutes, Quantitative Biosciences Institute, University of California, San Francisco]	8.20	28	Molecular systems biology	17	1	e8792
U01MH115747	Group 6					GSE155554,GSE155553,GSE155552				10.1016/j.neuron.2021.01.002	33497602	2021	Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience.	Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.	Animals;Autism Spectrum Disorder;Cerebral Cortex;Drug Evaluation, Preclinical;Estrogens;Female;Gene Expression Regulation, Developmental;Humans;Male;Neurogenesis;Risk Factors;Signal Transduction;Xenopus	Animals;Association;Autism Spectrum Disorder;Autistic Disorder;Biopharmaceuticals;Brain;Cerebral Cortex;Classification;Clustered Regularly Interspaced Short Palindromic Repeats;Drug Evaluation, Preclinical;Estrogens;Female;Gene Expression Regulation, Developmental;Gene Ontology;Genes;Genetics;Hedgehogs;Humans;In Silico;Knowledge;Lead;Male;Mutation;Neurogenesis;Neurons;Phenotype;Regulation;Risk;Risk Factors;Screening;Signal Transduction;Stem Cells;Telencephalon;Time;Xenopus	CRISPR;Xenopus tropicalis;autism spectrum disorders;brain development;convergent;estrogen;genetics;neural progenitor cells;neurogenesis;sonic hedgehog	Willsey, Helen Rankin;Exner, Cameron R T;Xu, Yuxiao;Everitt, Amanda;Sun, Nawei;Wang, Belinda;Dea, Jeanselle;Schmunk, Galina;Zaltsman, Yefim;Teerikorpi, Nia;Kim, Albert;Anderson, Aoife S;Shin, David;Seyler, Meghan;Nowakowski, Tomasz J;Harland, Richard M;Willsey, A Jeremy;State, Matthew W	[University of California, Berkeley, University of California, San Francisco];[University of California, San Francisco];[University of California, Berkeley, University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, Berkeley, University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, Berkeley];[Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco]	3.99	13	Neuron	109	5	788-804.e8
U01MH115747	Group 6	Technology								10.1038/s42003-021-02779-7	34737378	2021	Picroscope: low-cost system for simultaneous longitudinal biological imaging.	Simultaneous longitudinal imaging across multiple conditions and replicates has been crucial for scientific studies aiming to understand biological processes and disease. Yet, imaging systems capable of accomplishing these tasks are economically unattainable for most academic and teaching laboratories around the world. Here, we propose the Picroscope, which is the first low-cost system for simultaneous longitudinal biological imaging made primarily using off-the-shelf and 3D-printed materials. The Picroscope is compatible with standard 24-well cell culture plates and captures 3D z-stack image data. The Picroscope can be controlled remotely, allowing for automatic imaging with minimal intervention from the investigator. Here, we use this system in a range of applications. We gathered longitudinal whole organism image data for frogs, zebrafish, and planaria worms. We also gathered image data inside an incubator to observe 2D monolayers and 3D mammalian tissue culture models. Using this tool, we can measure the behavior of entire organisms or individual cells over long-time periods.	Animals;Behavior, Animal;Imaging, Three-Dimensional;Mammals;Organoids;Planarians;Xenopus;Zebrafish	Animals;Behavior;Behavior, Animal;Biological Processes;Biopharmaceuticals;Cell Culture Techniques;Cells;Cost;Culture;Disease;Imaging, Three-Dimensional;Incubators;Laboratories;Mammals;Measures;Organoids;Planarians;Research Personnel;Standards;Teaching;Time;Tissues;Xenopus;Zebrafish		Ly, Victoria T;Baudin, Pierre V;Pansodtee, Pattawong;Jung, Erik A;Voitiuk, Kateryna;Rosen, Yohei M;Willsey, Helen Rankin;Mantalas, Gary L;Seiler, Spencer T;Selberg, John A;Cordero, Sergio A;Ross, Jayden M;Rolandi, Marco;Pollen, Alex A;Nowakowski, Tomasz J;Haussler, David;Mostajo-Radji, Mohammed A;Salama, Sofie R;Teodorescu, Mircea	[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, San Francisco];[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, Santa Cruz];[University of California, San Francisco];[University of California, Santa Cruz];[University of California, San Francisco];[University of California, San Francisco];[Howard Hughes Medical Institute, University of California, Santa Cruz];[University of California, San Francisco, University of California, Santa Cruz];[Howard Hughes Medical Institute, University of California, Santa Cruz];[University of California, Santa Cruz]		1	Communications biology	4	1	1261
U01MH115747	Group 6									10.1093/cercor/bhab045	33822880	2021	Reductions in Gray Matter Linked to Epigenetic HIV-Associated Accelerated Aging.	A growing literature suggests a relationship between HIV-infection and a molecular profile of age acceleration. However, despite the widely known high prevalence of HIV-related brain atrophy and HIV-associated neurocognitive disorder (HAND), epigenetic age acceleration has not been linked to HIV-related changes in structural MRI. We applied morphological MRI methods to study the brain structure of 110 virally suppressed participants with HIV infection and 122 uninfected controls age 22-72. All participants were assessed for cognitive impairment, and blood samples were collected from a subset of 86 participants with HIV and 83 controls to estimate epigenetic age. We examined the group-level interactive effects of HIV and chronological age and then used individual estimations of epigenetic age to understand the relationship between age acceleration and brain structure. Finally, we studied the effects of HAND. HIV-infection was related to gray matter reductions, independent of age. However, using epigenetic age as a biomarker for age acceleration, individual HIV-related age acceleration was associated with reductions in total gray matter. HAND was associated with decreases in thalamic and hippocampal gray matter. In conclusion, despite viral suppression, accentuated gray matter loss is evident with HIV-infection, and greater biological age acceleration specifically relates to such gray matter loss.	AIDS Dementia Complex;Adult;Aged;Aging;Aging, Premature;Atrophy;Biomarkers;Brain;Epigenesis, Genetic;Female;Gray Matter;Hippocampus;Humans;Magnetic Resonance Imaging;Male;Middle Aged;Neuropsychological Tests;Thalamus;Young Adult	AIDS Dementia Complex;Acceleration;Adult;Aged;Aging;Aging, Premature;Atrophy;Biomarkers;Biopharmaceuticals;Blood;Brain;Cognitive Dysfunction;Epigenesis, Genetic;Epigenetics;Female;Gray Matter;HIV;HIV Infections;Hand;Hippocampus;Humans;Literature;Magnetic Resonance Imaging;Male;Methods;Middle Aged;Neurocognitive Disorders;Neuropsychological Tests;Prevalence;Thalamus;Young Adult	HAND;HIV;MRI;epigenetics	Lew, Brandon J;Schantell, Mikki D;O'Neill, Jennifer;Morsey, Brenda;Wang, Tina;Ideker, Trey;Swindells, Susan;Fox, Howard S;Wilson, Tony W	[Boys Town National Research Hospital, University of Nebraska Medical Center];[Boys Town National Research Hospital];;[University of Nebraska Medical Center];[University of California, San Diego];[University of California, San Diego];;[University of Nebraska Medical Center];[Boys Town National Research Hospital, University of Nebraska Medical Center]		3	Cerebral cortex (New York, N.Y. : 1991)	31	8	3752-3763
U01MH115747	Group 6	Genomics			Synapse::syn21392931,NeMO::dat-gnot1gb	GSE163018				10.1038/s41586-021-03209-8	34616060	2021	Single-cell epigenomics reveals mechanisms of human cortical development.	During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape1. In the developing brain, cell fate specification and topographic identity are important for defining cell identity2 and confer selective vulnerabilities to neurodevelopmental disorders3. Here, to identify cell-type-specific chromatin accessibility patterns in the developing human brain, we used a single-cell assay for transposase accessibility by sequencing (scATAC-seq) in primary tissue samples from the human forebrain. We applied unbiased analyses to identify genomic loci that undergo extensive cell-type- and brain-region-specific changes in accessibility during neurogenesis, and an integrative analysis to predict cell-type-specific candidate regulatory elements. We found that cerebral organoids recapitulate most putative cell-type-specific enhancer accessibility patterns but lack many cell-type-specific open chromatin regions that are found in vivo. Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.	Atlases as Topic;Brain;Chromatin;Disease Susceptibility;Enhancer Elements, Genetic;Epigenomics;Humans;Neurogenesis;Neurons;Organoids;Single-Cell Analysis;Tretinoin	ATAC-Seq;Atlases as Topic;Brain;Cells;Cerebral Cortex;Chromatin;Classification;Disease Susceptibility;Elements;Enhancer Elements, Genetic;Epigenomics;Genes, Regulator;Genomics;Humans;Neurodevelopmental Disorders;Neurogenesis;Neurons;Organoids;Prefrontal Cortex;Prosencephalon;Single-Cell Analysis;Stem Cells;Tissues;Transposases;Tretinoin		Ziffra, Ryan S;Kim, Chang N;Ross, Jayden M;Wilfert, Amy;Turner, Tychele N;Haeussler, Maximilian;Casella, Alex M;Przytycki, Pawel F;Keough, Kathleen C;Shin, David;Bogdanoff, Derek;Kreimer, Anat;Pollard, Katherine S;Ament, Seth A;Eichler, Evan E;Ahituv, Nadav;Nowakowski, Tomasz J	[Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of Washington School of Medicine];[Washington University School of Medicine];[University of California, Santa Cruz];[University of Maryland, School of Medicine];[Gladstone Institutes];[Health Sciences University (Turkey), University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[Computer Sciences, Department of Bioengineering and Therapeutic Sciences, University of California, Berkeley, University of California, San Francisco];[BioHub, Gladstone Institutes, Health Sciences University (Turkey), University of California, San Francisco];[University of Maryland, School of Medicine];[Howard Hughes Medical Institute, University of Washington, University of Washington School of Medicine];[Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco];[BioHub, University of California, San Francisco]	2.93	11	Nature	598	7879	205-213
U01MH115747	Group 6	Imaging								10.1126/sciadv.abf8142	34878844	2021	Superhuman cell death detection with biomarker-optimized neural networks.	Cellular events underlying neurodegenerative disease may be captured by longitudinal live microscopy of neurons. While the advent of robot-assisted microscopy has helped scale such efforts to high-throughput regimes with the statistical power to detect transient events, time-intensive human annotation is required. We addressed this fundamental limitation with biomarker-optimized convolutional neural networks (BO-CNNs): interpretable computer vision models trained directly on biosensor activity. We demonstrate the ability of BO-CNNs to detect cell death, which is typically measured by trained annotators. BO-CNNs detected cell death with superhuman accuracy and speed by learning to identify subcellular morphology associated with cell vitality, despite receiving no explicit supervision to rely on these features. These models also revealed an intranuclear morphology signal that is difficult to spot by eye and had not previously been linked to cell death, but that reliably indicates death. BO-CNNs are broadly useful for analyzing live microscopy and essential for interpreting high-throughput experiments.		Ability;Biomarkers;Biosensors;Cell Death;Cells;Computers;Death;Eye;Humans;Learning;Microscopy;Neurodegenerative Diseases;Neurons;Power, Psychological;Scales;Supervision;Time;Transients;Vision, Ocular		Linsley, Jeremy W;Linsley, Drew A;Lamstein, Josh;Ryan, Gennadi;Shah, Kevan;Castello, Nicholas A;Oza, Viral;Kalra, Jaslin;Wang, Shijie;Tokuno, Zachary;Javaherian, Ashkan;Serre, Thomas;Finkbeiner, Steven	[Gladstone Institutes];[Brown University];[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes];[Brown University];[Gladstone Institutes, University of California, San Francisco]		1	Science advances	7	50	eabf8142
U01MH115747	Group 6	Genomics				GSE180671				10.1242/dev.191619	34345915	2021	The atypical RNA-binding protein Taf15 regulates dorsoanterior neural development through diverse mechanisms in Xenopus tropicalis.	The FET family of atypical RNA-binding proteins includes Fused in sarcoma (FUS), Ewing's sarcoma (EWS) and the TATA-binding protein-associate factor 15 (TAF15). FET proteins are highly conserved, suggesting specialized requirements for each protein. Fus regulates splicing of transcripts required for mesoderm differentiation and cell adhesion in Xenopus, but the roles of Ews and Taf15 remain unknown. Here, we analyze the roles of maternally deposited and zygotically transcribed Taf15, which is essential for the correct development of dorsoanterior neural tissues. By measuring changes in exon usage and transcript abundance from Taf15-depleted embryos, we found that Taf15 may regulate dorsoanterior neural development through fgfr4 and ventx2.1. Taf15 uses distinct mechanisms to downregulate Fgfr4 expression, namely retention of a single intron within fgfr4 when maternal and zygotic Taf15 is depleted, and reduction in the total fgfr4 transcript when zygotic Taf15 alone is depleted. The two mechanisms of gene regulation (post-transcriptional versus transcriptional) suggest that Taf15-mediated gene regulation is target and co-factor dependent, contingent on the milieu of factors that are present at different stages of development.	Animals;Brain;Cell Differentiation;Exons;Female;Male;Neurogenesis;Neurons;RNA-Binding Proteins;TATA-Binding Protein Associated Factors;Xenopus	Animals;Brain;Cell Adhesion;Cell Differentiation;Embryo;Embryonic Development;Exons;Family;Female;Genes;Introns;Male;Mesoderm;Neurogenesis;Neurons;Proteins;RNA-Binding Proteins;RNA-Seq;Regulation;Role;Sarcoma;Sarcoma, Ewing;TATA-Binding Protein Associated Factors;TATA-Box Binding Protein;Tissues;Xenopus	           Xenopus         ;Embryo development;FET proteins;Maternal deposition;RNA-seq;Transcript regulation	DeJong, Caitlin S;Dichmann, Darwin S;Exner, Cameron R T;Xu, Yuxiao;Harland, Richard M	[University of California, Berkeley];[University of California, Berkeley];[Quantitative Biosciences Institute, University of California, San Francisco];[Quantitative Biosciences Institute, University of California, San Francisco];[University of California, Berkeley]		0	Development (Cambridge, England)	148	15
U01MH115747	Group 6									10.1101/pdb.prot105635	33827967	2021	Whole-Mount RNA In Situ Hybridization and Immunofluorescence of Xenopus Embryos and Tadpoles.	A major advantage of experimentation in Xenopus is the ability to query the localization of endogenous proteins and RNAs in situ in the entire animal during all of development. Here I describe three variations of staining to visualize mRNAs and proteins in developing Xenopus embryos and tadpoles. The first section outlines a traditional colorimetric staining for mRNAs that is suitable for all stages of development, and the second extends this protocol for fluorescence-based detection for higher spatial and quantitative resolution. The final section details detection of proteins by immunofluorescence, optimized for tadpole stages but widely applicable to others. Finally, optimization strategies are provided.	Animals;Fluorescent Antibody Technique;In Situ Hybridization;Larva;RNA;RNA, Messenger;Xenopus laevis	Ability;Animals;Embryo;Fluorescence;Fluorescent Antibody Technique;Immunofluorescence;In Situ Hybridization;Larva;Outline;Proteins;RNA;RNA, Messenger;Staining;Tadpole;Xenopus;Xenopus laevis		Willsey, Helen Rankin	University of California, San Francisco		1	Cold Spring Harbor protocols	2021	10
U01MH115747	Group 6	Review								10.1002/dvg.23405	33369095	2021	Xenopus leads the way: Frogs as a pioneering model to understand the human brain.	From its long history in the field of embryology to its recent advances in genetics, Xenopus has been an indispensable model for understanding the human brain. Foundational studies that gave us our first insights into major embryonic patterning events serve as a crucial backdrop for newer avenues of investigation into organogenesis and organ function. The vast array of tools available in Xenopus laevis and Xenopus tropicalis allows interrogation of developmental phenomena at all levels, from the molecular to the behavioral, and the application of CRISPR technology has enabled the investigation of human disorder risk genes in a higher-throughput manner. As the only major tetrapod model in which all developmental stages are easily manipulated and observed, frogs provide the unique opportunity to study organ development from the earliest stages. All of these features make Xenopus a premier model for studying the development of the brain, a notoriously complex process that demands an understanding of all stages from fertilization to organogenesis and beyond. Importantly, core processes of brain development are conserved between Xenopus and human, underlining the advantages of this model. This review begins by summarizing discoveries made in amphibians that form the cornerstones of vertebrate neurodevelopmental biology and goes on to discuss recent advances that have catapulted our understanding of brain development in Xenopus and in relation to human development and disease. As we engage in a new era of patient-driven gene discovery, Xenopus offers exceptional potential to uncover conserved biology underlying human brain disorders and move towards rational drug design.	Animals;Brain;Disease Models, Animal;Neurogenesis;Xenopus laevis	Amphibians;Animals;Biology;Brain;Brain Diseases;Candidate Gene Identification;Clustered Regularly Interspaced Short Palindromic Repeats;Comprehension;Congenital Abnormalities;Disease;Disease Models, Animal;Drug Design;Embryology;Fertilization;Form;Genes;Genetics;History;Human Development;Humans;Lead;Neurogenesis;News;Organogenesis;Patients;Review;Risk;Technology;Vertebrates;Xenopus;Xenopus laevis	amphibian;birth defects;genetics;neural;organogenesis	Exner, Cameron R T;Willsey, Helen Rankin	[University of California, San Francisco];[University of California, San Francisco]	1.34	5	Genesis (New York, N.Y. : 2000)	59	1-2	e23405
U01MH115747	Group 6	Genomics						phs002624.v2.p1		10.1126/science.abi7377	35084939	2022	A single-cell atlas of the normal and malformed human brain vasculature.	Cerebrovascular diseases are a leading cause of death and neurologic disability. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of cerebrovascular cells in humans. We profiled transcriptomes of 181,388 cells to define a cell atlas of the adult human cerebrovasculature, including endothelial cell molecular signatures with arteriovenous segmentation and expanded perivascular cell diversity. By leveraging this reference, we investigated cellular and molecular perturbations in brain arteriovenous malformations, which are a leading cause of stroke in young people, and identified pathologic endothelial transformations with abnormal vascular patterning and the ontology of vascularly derived inflammation. We illustrate the interplay between vascular and immune cells that contributes to brain hemorrhage and catalog opportunities for targeting angiogenic and inflammatory programs in vascular malformations.	Adult;Blood Vessels;Brain;Cells, Cultured;Cerebral Cortex;Cerebral Hemorrhage;Cerebrovascular Circulation;Endothelial Cells;Fibroblasts;Humans;Inflammation;Intracranial Arteriovenous Malformations;Monocytes;Muscle, Smooth, Vascular;Pericytes;RNA-Seq;Single-Cell Analysis;Transcriptome	Adult;Arteriovenous Malformations;Atlas;Blood Vessels;Brain;Brain Hemorrhage;Catalog;Cause of Death;Cells;Cells, Cultured;Cerebral Cortex;Cerebral Hemorrhage;Cerebrovascular Circulation;Cerebrovascular Disorders;Comprehension;Disease;Endothelial Cells;Fibroblasts;Humans;Inflammation;Intracranial Arteriovenous Malformations;Knowledge;Monocytes;Muscle, Smooth, Vascular;Pericytes;Persons;Program;RNA-Seq;Single-Cell Analysis;Stroke;Therapeutics;Transcriptome;Vascular Malformations		Winkler, Ethan A;Kim, Chang N;Ross, Jayden M;Garcia, Joseph H;Gil, Eugene;Oh, Irene;Chen, Lindsay Q;Wu, David;Catapano, Joshua S;Raygor, Kunal;Narsinh, Kazim;Kim, Helen;Weinsheimer, Shantel;Cooke, Daniel L;Walcott, Brian P;Lawton, Michael T;Gupta, Nalin;Zlokovic, Berislav V;Chang, Edward F;Abla, Adib A;Lim, Daniel A;Nowakowski, Tomasz J	[Barrow Neurological Institute, University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];;;[University of California, San Francisco];[Barrow Neurological Institute];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[NorthShore University HealthSystem];[Barrow Neurological Institute];[University of California, San Francisco];[Keck School of Medicine, University of Southern California, Zilkha Neurogenetic Institute];[University of California, San Francisco];[University of California, San Francisco];[San Francisco VA Medical Center, University of California, San Francisco];[BioHub, University of California, San Francisco]		1	Science (New York, N.Y.)	375	6584	eabi7377
U01MH115747	Group 6	Review								10.1038/s41576-021-00441-w	35013567	2022	From systems to structure - using genetic data to model protein structures.	Understanding the effects of genetic variation is a fundamental problem in biology that requires methods to analyse both physical and functional consequences of sequence changes at systems-wide and mechanistic scales. To achieve a systems view, protein interaction networks map which proteins physically interact, while genetic interaction networks inform on the phenotypic consequences of perturbing these protein interactions. Until recently, understanding the molecular mechanisms that underlie these interactions often required biophysical methods to determine the structures of the proteins involved. The past decade has seen the emergence of new approaches based on coevolution, deep mutational scanning and genome-scale genetic or chemical-genetic interaction mapping that enable modelling of the structures of individual proteins or protein complexes. Here, we review the emerging use of large-scale genetic datasets and deep learning approaches to model protein structures and their interactions, and discuss the integration of structural data from different sources.	Epistasis, Genetic;Gene Regulatory Networks;Mutation;Protein Interaction Mapping;Protein Interaction Maps;Proteins	Biology;Comprehension;Dataset;Deep Learning;Epistasis, Genetic;Gene Regulatory Networks;Genetic Variation;Genetics;Genome;Map;Methods;Mutation;News;Protein Interaction Mapping;Protein Interaction Maps;Proteins;Review;Scales		Braberg, Hannes;Echeverria, Ignacia;Kaake, Robyn M;Sali, Andrej;Krogan, Nevan J	[Quantitative Biosciences Institute, University of California, San Francisco];[Department of Bioengineering and Therapeutic Sciences, Quantitative Biosciences Institute, University of California, San Francisco];[Gladstone Institutes, Quantitative Biosciences Institute, University of California, San Francisco];[Department of Bioengineering and Therapeutic Sciences, Quantitative Biosciences Institute, University of California, San Francisco];[Gladstone Institutes, Icahn School of Medicine, Quantitative Biosciences Institute, University of California, San Francisco]		0	Nature reviews. Genetics	23	6	342-354
U01MH115747	Group 6	Genomics				GSE187875,GSE171592,GSE171591,GSE171589,GSE171584,GSE171523		phs002624.v1.p1		10.1038/s41586-021-04230-7	34912114	2022	Individual human cortical progenitors can produce excitatory and inhibitory neurons.	The cerebral cortex is a cellularly complex structure comprising a rich diversity of neuronal and glial cell types. Cortical neurons can be broadly categorized into two classes-excitatory neurons that use the neurotransmitter glutamate, and inhibitory interneurons that use γ-aminobutyric acid (GABA). Previous developmental studies in rodents have led to a prevailing model in which excitatory neurons are born from progenitors located in the cortex, whereas cortical interneurons are born from a separate population of progenitors located outside the developing cortex in the ganglionic eminences1-5. However, the developmental potential of human cortical progenitors has not been thoroughly explored. Here we show that, in addition to excitatory neurons and glia, human cortical progenitors are also capable of producing GABAergic neurons with the transcriptional characteristics and morphologies of cortical interneurons. By developing a cellular barcoding tool called 'single-cell-RNA-sequencing-compatible tracer for identifying clonal relationships' (STICR), we were able to carry out clonal lineage tracing of 1,912 primary human cortical progenitors from six specimens, and to capture both the transcriptional identities and the clonal relationships of their progeny. A subpopulation of cortically born GABAergic neurons was transcriptionally similar to cortical interneurons born from the caudal ganglionic eminence, and these cells were frequently related to excitatory neurons and glia. Our results show that individual human cortical progenitors can generate both excitatory neurons and cortical interneurons, providing a new framework for understanding the origins of neuronal diversity in the human cortex.	Cell Lineage;Cerebral Cortex;GABAergic Neurons;Humans;Interneurons;Neural Inhibition;Neurons	Cell Lineage;Cells;Cerebral Cortex;Comprehension;GABAergic Neurons;Glutamates;Humans;Interneurons;Neural Inhibition;Neuroglia;Neurons;Neurotransmitters;News;Population;Rodentia;Sequence Determinations, RNA;gamma-Aminobutyric Acid		Delgado, Ryan N;Allen, Denise E;Keefe, Matthew G;Mancia Leon, Walter R;Ziffra, Ryan S;Crouch, Elizabeth E;Alvarez-Buylla, Arturo;Nowakowski, Tomasz J	[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[University of California, San Francisco];[BioHub, University of California, San Francisco]		5	Nature	601	7893	397-403
U01MH115747	Group 6	Protocol								10.1101/pdb.prot106997	34531330	2022	Modeling Human Genetic Disorders with CRISPR Technologies in Xenopus.	Combining the power of Xenopus developmental biology with CRISPR-based technologies promises great discoveries in understanding and treating human genetic disorders. Here we provide a practical pipeline for how to go from known disease gene(s) or risk gene(s) of interest to methods for gaining functional insight into the contribution of these genes to disorder etiology in humans.	Animals;CRISPR-Cas Systems;Gene Editing;Humans;Xenopus laevis	Animals;CRISPR-Cas Systems;Clustered Regularly Interspaced Short Palindromic Repeats;Comprehension;Developmental Biology;Disease;Gene Editing;Genes;Human Genetics;Humans;Methods;Power, Psychological;Risk;Technology;Xenopus;Xenopus laevis		Willsey, Helen Rankin;Guille, Matthew;Grainger, Robert M	[University of California, San Francisco, University of Virginia];[University of Portsmouth];[University of California, San Francisco, University of Virginia]		0	Cold Spring Harbor protocols	2022	3
U01MH115747	Group 6	Proteimics				GSE159411			PXD022091	10.1016/j.cell.2022.01.021	35182466	2022	Transcription factor protein interactomes reveal genetic determinants in heart disease.	Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.	Animals;GATA4 Transcription Factor;Heart Defects, Congenital;Mice;Mutation;Nuclear Proteins;Oxidoreductases;Proteomics;T-Box Domain Proteins;Transcription Factors	Animals;Disease;Epigenetics;Exome;GATA4 Transcription Factor;Genes;Genes, Developmental;Genetics;Heart Defects, Congenital;Heart Diseases;Humans;In Vitro;Live Birth;Mice;Mutation;Nuclear Proteins;Oxidoreductases;Parents;Proteins;Proteomics;T-Box Domain Proteins;Transcription Factors	GATA4;GLYR1;NPAC;TBX5;congenital heart disease;de novo variants;disease variants;genetics;protein interactome networks	Gonzalez-Teran, Barbara;Pittman, Maureen;Felix, Franco;Thomas, Reuben;Richmond-Buccola, Desmond;Hüttenhain, Ruth;Choudhary, Krishna;Moroni, Elisabetta;Costa, Mauro W;Huang, Yu;Padmanabhan, Arun;Alexanian, Michael;Lee, Clara Youngna;Maven, Bonnie E J;Samse-Knapp, Kaitlen;Morton, Sarah U;McGregor, Michael;Gifford, Casey A;Seidman, J G;Seidman, Christine E;Gelb, Bruce D;Colombo, Giorgio;Conklin, Bruce R;Black, Brian L;Bruneau, Benoit G;Krogan, Nevan J;Pollard, Katherine S;Srivastava, Deepak	[Gladstone Institutes];[Gladstone Institutes, University of California, San Francisco];[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes, Quantitative Biosciences Institute, University of California, San Francisco];[Gladstone Institutes];;[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes, University of California, San Francisco];[Gladstone Institutes];[Gladstone Institutes];[Gladstone Institutes, University of California, San Francisco];[Gladstone Institutes];[Boston Children's Hospital, Harvard Medical School];[Gladstone Institutes, Quantitative Biosciences Institute, University of California, San Francisco];[Gladstone Institutes];[Harvard Medical School];[Brigham and Women's Hospital, Harvard Medical School, Howard Hughes Medical Institute];[Icahn School of Medicine, Mindich Child Health and Development Institute];[University of Pavia];[Gladstone Institutes];[UCSF Cardiovascular Research Institute];[Gladstone Institutes, UCSF Cardiovascular Research Institute, UCSF School of Medicine];[Gladstone Institutes, Quantitative Biosciences Institute, University of California, San Francisco];[BioHub, Gladstone Institutes, University of California, San Francisco];[Gladstone Institutes, UCSF School of Medicine, University of California, San Francisco]		2	Cell	185	5	794-814.e30
U01MH121499	Group 7	Proteomics							PXD022667	10.1038/s41467-021-22648-5	33972534	2021	Genoppi is an open-source software for robust and standardized integration of proteomic and genetic data.	Combining genetic and cell-type-specific proteomic datasets can generate biological insights and therapeutic hypotheses, but a technical and statistical framework for such analyses is lacking. Here, we present an open-source computational tool called Genoppi (lagelab.org/genoppi) that enables robust, standardized, and intuitive integration of quantitative proteomic results with genetic data. We use Genoppi to analyze 16 cell-type-specific protein interaction datasets of four proteins (BCL2, TDP-43, MDM2, PTEN) involved in cancer and neurological disease. Through systematic quality control of the data and integration with published protein interactions, we show a general pattern of both cell-type-independent and cell-type-specific interactions across three cancer cell types and one human iPSC-derived neuronal cell type. Furthermore, through the integration of proteomic and genetic datasets in Genoppi, our results suggest that the neuron-specific interactions of these proteins are mediating their genetic involvement in neurodegenerative diseases. Importantly, our analyses suggest that human iPSC-derived neurons are a relevant model system for studying the involvement of BCL2 and TDP-43 in amyotrophic lateral sclerosis.	Cell Line, Tumor;Cells, Cultured;Computational Biology;DNA-Binding Proteins;Genome-Wide Association Study;Genomics;Humans;Induced Pluripotent Stem Cells;Mutation;Neoplasms;Neurons;Polymorphism, Single Nucleotide;Protein Binding;Proteomics;Proto-Oncogene Proteins c-bcl-2;Proto-Oncogene Proteins c-mdm2;Software;Tandem Mass Spectrometry	Amyotrophic Lateral Sclerosis;B-Cell Leukemia 2 Family Proteins;Binding Proteins;Biopharmaceuticals;Cancer;Cell Line, Tumor;Cells;Cells, Cultured;Classification;Computational Biology;DNA-Binding Proteins;Dataset;Disease;Genetics;Genome-Wide Association Study;Genomics;Humans;Induced Pluripotent Stem Cells;Mediating;Mutation;Neoplasms;Neurodegenerative Diseases;Neurons;Polymorphism, Single Nucleotide;Proteins;Proteomics;Proto-Oncogene Proteins c-bcl-2;Proto-Oncogene Proteins c-mdm2;Quality Control;Software;Tandem Mass Spectrometry;Therapeutics		Pintacuda, Greta;Lassen, Frederik H;Hsu, Yu-Han H;Kim, April;Martín, Jacqueline M;Malolepsza, Edyta;Lim, Justin K;Fornelos, Nadine;Eggan, Kevin C;Lage, Kasper	[Broad Institute of MIT and Harvard, Harvard University];[Broad Institute of MIT and Harvard, Massachusetts General Hospital, Nuffield Department of Clinical Medicine, University of Oxford, Wellcome Centre for Human Genetics];[Broad Institute of MIT and Harvard, Massachusetts General Hospital];[Broad Institute of MIT and Harvard, Johns Hopkins University, Massachusetts General Hospital];[Broad Institute of MIT and Harvard, Harvard University];[Broad Institute of MIT and Harvard, Massachusetts General Hospital];[Broad Institute of MIT and Harvard, Massachusetts General Hospital, Massachusetts Institute of Technology];[Broad Institute of MIT and Harvard, Massachusetts General Hospital];[Broad Institute of MIT and Harvard, Harvard University];[Broad Institute of MIT and Harvard, Kurume University, Massachusetts General Hospital]		1	Nature communications	12	1	2580
U01MH121499	Group 7	Genomics								10.1038/s41467-021-25014-7	34489429	2021	Translating polygenic risk scores for clinical use by estimating the confidence bounds of risk prediction.	A promise of genomics in precision medicine is to provide individualized genetic risk predictions. Polygenic risk scores (PRS), computed by aggregating effects from many genomic variants, have been developed as a useful tool in complex disease research. However, the application of PRS as a tool for predicting an individual's disease susceptibility in a clinical setting is challenging because PRS typically provide a relative measure of risk evaluated at the level of a group of people but not at individual level. Here, we introduce a machine-learning technique, Mondrian Cross-Conformal Prediction (MCCP), to estimate the confidence bounds of PRS-to-disease-risk prediction. MCCP can report disease status conditional probability value for each individual and give a prediction at a desired error level. Moreover, with a user-defined prediction error rate, MCCP can estimate the proportion of sample (coverage) with a correct prediction.	Age Factors;Biological Specimen Banks;Breast Neoplasms;Coronary Artery Disease;Diabetes Mellitus, Type 2;Female;Genetic Predisposition to Disease;Humans;Inflammatory Bowel Diseases;Machine Learning;Male;Multifactorial Inheritance;Reproducibility of Results;Schizophrenia;Sweden;United Kingdom	Age Factors;Biological Specimen Banks;Breast Neoplasms;Coronary Artery Disease;Diabetes Mellitus, Type 2;Disease;Disease Susceptibility;Female;Genetic Predisposition to Disease;Genetics;Genomics;Humans;Inflammatory Bowel Diseases;Machine Learning;Male;Measures;Multifactorial Inheritance;Persons;Precision Medicine;Probability;Relatives;Report;Reproducibility of Results;Research;Risk;Risk Scores;Schizophrenia;Sweden;Translating;United Kingdom		Sun, Jiangming;Wang, Yunpeng;Folkersen, Lasse;Borné, Yan;Amlien, Inge;Buil, Alfonso;Orho-Melander, Marju;Børglum, Anders D;Hougaard, David M;;Melander, Olle;Engström, Gunnar;Werge, Thomas;Lage, Kasper	[H. Lundbeck A/S, Lund University];[University of Oslo];[H. Lundbeck A/S];[Lund University];[University of Oslo];[H. Lundbeck A/S];[Lund University];[Aarhus University, H. Lundbeck A/S];[H. Lundbeck A/S, Statens Serum Institut];;[Lund University];[Lund University];[H. Lundbeck A/S, University of Copenhagen];[Broad Institute of MIT and Harvard, Kurume University, Massachusetts General Hospital]		1	Nature communications	12	1	5276