Human neuroepithelial stem cell regional specificity enables spinal cord repair through a relay circuit

Traumatic spinal cord injury results in persistent disability due to disconnection of surviving neural elements. Neural stem cell transplantation has been proposed as a therapeutic option, but optimal cell type and mechanistic aspects remain poorly defined. Here, we describe robust engraftment into lesioned immunodeficient mice of human neuroepithelial stem cells derived from the developing spinal cord and maintained in self-renewing adherent conditions for long periods. Extensive elongation of both graft and host axons occurs. Improved functional recovery after transplantation depends on neural relay function through the grafted neurons, requires the matching of neural identity to the anatomical site of injury, and is accompanied by expression of specific marker proteins. Thus, human neuroepithelial stem cells may provide an anatomically specific relay function for spinal cord injury recovery

Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures

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Comparative transcriptome and gene regulation in human iPSC-derived organoids and donor-identical brain tissue

Modeling human brain development in vitro is critically important to understand the pathophysiology of neuropsychiatric disorders. As part of the PsychENCODE project, we generated human induced pluripotent stem cells (hiPSCs) from skin fibroblasts of three human specimens at 15, 16 and 17 postconceptional weeks. These hiPSC were differentiated into telencephalic organoids to study early genetic programs in forebrain development. By using RNA-seq and histone chromatin immunoprecipitation (ChIP-seq), we compared transcriptomes and epigenomes of hiPSCs-derived organoids to donor-identical cortical brain tissue. Immunocytochemical characterization of the organoids over a time course (TD0, TD11 and TD30) showed expression of radial glial markers and mature cortical neurons confirming telencephalic fate. Hierarchical clustering of the organoids’ transcriptomes demonstrated stage-specific patterns of gene expression during in vitro development. Mapping organoids’ transcriptomes against the BrainSpan dataset suggested highest correlations with neocortex and showed their correspondence to post-conceptional weeks 8-16 of human fetal development. We then inferred transcriptional alterations, by differential gene expression, between organoids and the two brain regions analyzed. We found ~5000 of differentially expressed genes (DEG) between TD0 and fetal cortex and a decreasing number of DEG at TD11 and TD30 suggesting a stronger, albeit incomplete similarity of the organoids to the cortex at later time points. ChIP-seq experiments identified H3K27ac and H3K4me3 peaks (putative promoters and enhancers) differentially active at different organoids developmental stages and between organoids and fetal brain. Overall, however, hierarchical clustering of H3K27ac and H3K4me3 peaks demonstrated clustering of organoids with human fetal brain samples from various databases, whereas neonatal and adult brain samples formed separate clusters. These data suggest that organoids recapitulate in part transcriptome and epigenome features of fetal human brain

Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia

Graphical Abstract Highlights d Derivation of human neocortical and spinal cord neuroepithelial stem (NES) cells d Zika virus (ZIKV) infects NES cells and radial glia, impairing mitosis and survival d ZIKV induces mitochondrial sequestration of centrosomal phospho-TBK1 d Nucleoside analogs inhibit ZIKV replication, protecting NES cells from cell death In Brief Onorati et al. establish neuroepithelial stem (NES) cells as a model for studying human neurodevelopment and ZIKV-induced microcephaly. Together with analyses in human brain slices and microcephalic human fetal tissue, they find that ZIKV predominantly infects NES and radial glial cells, reveal a pivotal role for pTBK1, and find that nucleoside analogs inhibit ZIKV replication, protecting NES cells from cell death

Neural stem cells direct axon guidance via their radial fiber scaffold

Neural stem cells directly or indirectly generate all neurons and macroglial cells and guide migrating neurons by using a palisade-like scaffold made of their radial fibers. Here, we describe an unexpected role for the radial fiber scaffold in directing corticospinal and other axons at the junction between the striatum and globus pallidus. The maintenance of this scaffold, and consequently axon pathfinding, is dependent on the expression of an atypical RHO-GTPase, RND3/RHOE, together with its binding partner ARHGAP35/P190A, a RHO GTPase-activating protein, in the radial glia-like neural stem cells within the ventricular zone of the medial ganglionic eminence. This role is independent of RND3 and ARHGAP35 expression in corticospinal neurons, where they regulate dendritic spine formation, axon elongation, and pontine midline crossing in a FEZF2-dependent manner. The prevalence of neural stem cell scaffolds and their expression of RND3 and ARHGAP35 suggests that these observations might be broadly relevant for axon guidance and neural circuit formation.This work was supported by Labex LifeSenses grants ANR-10-LABX-65 and ANR-11-IDEX-0004-02 to A.C.; MINECO SAF2013-49176-C2-1-R and Programa Santander-FUSP to I.P.-R. and J.T.; NIH grants R01 MH115939, NS105640, and NS089662 to A.J.K.; and NIH grants MH103339, MH106934, MH110926, and MH109904 to N.S. Additional support was provided by the Kavli Foundation and the Simons Foundation.Peer reviewe

Transcriptional Landscape of the Prenatal Human Brain

Summary The anatomical and functional architecture of the human brain is largely determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and postmitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and human-expanded outer subventricular zones. Both germinal and postmitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in frontal lobe. Finally, many neurodevelopmental disorder and human evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development

Integrative functional genomic analysis of human brain development and neuropsychiatric risks

INTRODUCTION The brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders. RATIONALE The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain. RESULTS Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes including MEF2C, SATB2, and TCF4, with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity. CONCLUSION We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease