Project description:The cerebral cortex plays an important role in cognitive function and specialized perception in mammals and its development requires highly specific spatio-temporal control of gene expression. The study identified stage- and region-specific markers throughout cerebral corticogenesis at various important stages of cerebral cortex development; embryonic day (E) 15.5, E17.5, postnatal day (P) 1.5 and 4-6 months old. The study involved the analysis of 12 SAGE libraries, which were generated from the mouse cerebral cortex of E15.5 (n=3), E17.5 (n=2), P1.5 (n=1) and 4-6 month old (n=6). N denotes biological replicates.
Project description:Many neurological and psychiatric disorders affect the cerebral cortex, and a clearer understanding of the molecular processes underlying human corticogenesis will provide greater insight into such pathologies. To date, knowledge of gene expression changes accompanying corticogenesis is largely based on murine data. Here we present a searchable, comprehensive, temporal gene expression dataset encompassing cerebral cortical development from human embryonic stem cells (hESCs). Using a modified differentiation protocol and RNA-Seq technology with computational analysis, we identified sets of genes and long non-coding RNAs that significantly change during corticogenesis, and those enriched for disease-associations. Numerous alternatively-spliced genes with varying temporal patterns of expression are revealed, including TGIF1, involved in holoprosencephaly and MARK1, involved in autism. We have created a database (http://cortecon.neuralsci.org) that provides online, query-based access to changes in RNA expression and alternatively spliced transcripts during human cortical development. Nine timepoints (days 0,7,12,19,26,33,49,63,77) covering human corticogenesis from embyronic stem cells.
Project description:The double-stranded RNA binding protein (RBP) STAU2 displays temporally regulated associations with RNA determinants that contribute to IPC and cortical lamination during corticogenesis.
Project description:The cerebral cortex plays an important role in cognitive function and specialized perception in mammals and its development requires highly specific spatio-temporal control of gene expression. The study identified stage- and region-specific markers throughout cerebral corticogenesis at various important stages of cerebral cortex development; embryonic day (E) 15.5, E17.5, postnatal day (P) 1.5 and 4-6 months old.
Project description:Evolutionary changes in gene regulation during cortical development likely contributed to the expansion and specialization of the cortex. However, the lack of a regulatory map of the embryonic cortex has hindered identification of these changes and the biological processes they influenced. We performed genome-wide epigenetic profiling to compare promoter and enhancer activity during corticogenesis in rhesus and mouse. We identified 2,855 promoters and 8,996 enhancers that have gained activity in based on increased epigenetic marking. To detect biological pathways enriched for these changes, we mapped promoters and enhancers exhibiting epigenetic gains onto modules of co-expressed genes constructed using spatio-temporally rich expression data from developing cortex. We identified multiple modules enriched in lineage epigenetic gains. Gains in enriched modules were associated with genes functioning in neuronal proliferation and migration, cortical patterning, and the extracellular matrix. Gain-enriched modules also showed correlated gene expression patterns and similar transcription factor binding site enrichments in promoters and enhancers, suggesting they are connected by common regulatory mechanisms. Our results reveal coordinated patterns of potential regulatory changes associated with conserved developmental processes in corticogenesis, providing insight into cortical evolution.
Project description:Evolutionary changes in gene regulation during cortical development likely contributed to the expansion and specialization of the cortex in humans. However, the lack of a regulatory map of the human embryonic cortex has hindered identification of these changes and the biological processes they influenced. We performed genome-wide epigenetic profiling to compare promoter and enhancer activity during corticogenesis in human, rhesus, and mouse. We identified 2,855 promoters and 8,996 enhancers that have gained activity in human based on increased epigenetic marking. To detect biological pathways enriched for these changes, we mapped promoters and enhancers exhibiting epigenetic gains onto modules of co-expressed genes constructed using spatio-temporally rich expression data from developing human cortex. We identified multiple modules enriched in human lineage epigenetic gains. Gains in enriched modules were associated with genes functioning in neuronal proliferation and migration, cortical patterning, and the extracellular matrix. Gain-enriched modules also showed correlated gene expression patterns and similar transcription factor binding site enrichments in promoters and enhancers, suggesting they are connected by common regulatory mechanisms. Our results reveal coordinated patterns of potential regulatory changes associated with conserved developmental processes in corticogenesis, providing insight into human cortical evolution.
Project description:Many neurological and psychiatric disorders affect the cerebral cortex, and a clearer understanding of the molecular processes underlying human corticogenesis will provide greater insight into such pathologies. To date, knowledge of gene expression changes accompanying corticogenesis is largely based on murine data. Here we present a searchable, comprehensive, temporal gene expression dataset encompassing cerebral cortical development from human embryonic stem cells (hESCs). Using a modified differentiation protocol and RNA-Seq technology with computational analysis, we identified sets of genes and long non-coding RNAs that significantly change during corticogenesis, and those enriched for disease-associations. Numerous alternatively-spliced genes with varying temporal patterns of expression are revealed, including TGIF1, involved in holoprosencephaly and MARK1, involved in autism. We have created a database (http://cortecon.neuralsci.org) that provides online, query-based access to changes in RNA expression and alternatively spliced transcripts during human cortical development.
Project description:In the developing cerebral cortex different types of neurons and glial cells are born through a precisely controlled sequence of events. The fate of cortical progenitors, in turn, is determined by an elusive conundrum of temporally and spatially regulated signalling mechanisms. We found the DNA-binding transcription factor Sip1 (also known as Zfhx1b) to be produced at high levels in postmitotic neurons of the cerebral cortex. Conditional deletion of Sip1 in young neocortical neurons was found to induce premature and increased production of upper layer neurons at the expense of deep layer neurons. Furthermore, it caused precocious and increased generation of glial precursors during late corticogenesis, leading subsequently to enhanced astrocytogenesis at early postnatal stages. Expression profiling analysis indicated that the temporal shift in upper layer production coincides with overexpression of the neurotrophin-3 (NT3) gene and altered growth factor signalling in progenitors, while the premature gliogenesis is preceded by upregulation of fibroblast growth factor-9 (Fgf9) gene expression. Chromatin immunoprecipitation and in situ hybridization validates NT3 as a direct target of Sip1 in the cortex and confines the transcriptional repression by Sip1 to postmitotic neurons. Moreover, we show that exogenous application of Fgf9 in solution or via coated beads to wild-type cortical slices induces premature and excessive generation of glial precursors in the germinal zone. In conclusion, our data suggest that throughout corticogenesis Sip1 acts to restrain the level of production of secreted signalling factors in postmitotic neurons. These factors feed back to progenitor cells in order to regulate the timing of cell fate switch and the numbers of neurons and glial cells produced in the developing cerebral cortex.
Project description:The mammalian cerebral cortex has an unparalleled diversity of cell types, which are generated during development through a series of temporally orchestrated events that are under tight evolutionary constraint and are critical for proper cortical assembly and function. However, the molecular logic that governs the establishment and organization of cortical cell types remains elusive, largely due to the large number of cell classes undergoing dynamic cell-state transitions over extended developmental timelines. Here, we have generated a comprehensive single-cell RNA-seq and single-cell ATAC-seq atlas of the developing mouse neocortex, sampled every day throughout embryonic corticogenesis and at early postnatal ages, complemented with a spatial transcriptomics time-course. We computationally reconstruct developmental trajectories across the diversity of cortical cell classes, and infer their spatial organization and the gene regulatory programs that accompany their lineage bifurcation decisions and differentiation trajectories. Finally, we demonstrate how this developmental map pinpoints the origin of lineage-specific developmental abnormalities linked to aberrant corticogenesis in mutant animals. The data provides a global picture of the regulatory mechanisms governing cellular diversification in the neocortex.
Project description:The mammalian cerebral cortex has an unparalleled diversity of cell types, which are generated during development through a series of temporally orchestrated events that are under tight evolutionary constraint and are critical for proper cortical assembly and function. However, the molecular logic that governs the establishment and organization of cortical cell types remains elusive, largely due to the large number of cell classes undergoing dynamic cell-state transitions over extended developmental timelines. Here, we have generated a comprehensive single-cell RNA-seq and single-cell ATAC-seq atlas of the developing mouse neocortex, sampled every day throughout embryonic corticogenesis and at early postnatal ages, complemented with a spatial transcriptomics time-course. We computationally reconstruct developmental trajectories across the diversity of cortical cell classes, and infer their spatial organization and the gene regulatory programs that accompany their lineage bifurcation decisions and differentiation trajectories. Finally, we demonstrate how this developmental map pinpoints the origin of lineage-specific developmental abnormalities linked to aberrant corticogenesis in mutant animals. The data provides a global picture of the regulatory mechanisms governing cellular diversification in the neocortex.