Lineage Progression of Cortical Neural Stem Cells

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Formation of functional neural circuits depends on the proper generation of different neuronal and glial cell types in the correct numbers and order. In the developing mammalian central nervous system, multipotent neural stem cells initially produce neurons, followed by glia. The cerebral cortex is the brain region that best exemplifies this developmental theme. In the developing cortex, multipotent neural stem cells, known as the radial glial cells (RGCs), sequentially generate the diverse cortical excitatory neuronal subtypes that populate different cortical layers. At the end of cortical neurogenesis, the RGCs switch lineages and generate inhibitory olfactory bulb interneurons, and both types of cortical macroglia. The cellular process and molecular mechanisms that underlie this lineage switch is not known. Lack of this knowledge hinders our effort to understand the etiology of various neurodevelopmental disorders. In this grant application, we propose to determine the lineage segregation patterns among OB interneuron, astrocyte and oligodendrocyte lineages (Aim 1), to investigate whether Shh signaling regulates lineage specification of cortical astrocytes (Aim 2), and to uncover the underlying molecular mechanisms underlying the lineage switch of cortical RGCs (Aims 2 and 3). We will combine mouse genetics, MADM and intersectional lineage analyses, RNA-seq, single-cell RNA-seq, ChIP-seq, CUT&RUN, ATAC-seq, and 4C technologies to achieve these goals.