Lineage Progression of Cortical Neural Stem Cells

功能性神经回路的形成取决于不同的神经元的适当生成。 神经元和神经胶质细胞类型以正确的数量和顺序。在发展中 哺乳动物中枢神经系统，多能神经干细胞最初产生 神经元，其次是神经胶质。大脑皮层是最能体现这一点的大脑区域 发展主题。在发育中的大脑皮层中，多能神经干细胞， 放射状神经胶质细胞（RGC），依次产生不同的皮质兴奋性神经元 不同类型的大脑皮层。在皮质神经发生的末期， RGCs转换谱系并产生抑制性嗅球中间神经元， 大脑皮层大胶质细胞这背后的细胞过程和分子机制 世系切换是未知的。缺乏这方面的知识阻碍了我们努力了解 各种神经发育障碍的病因学。在这项拨款申请中，我们建议 确定OB中间神经元、星形胶质细胞和 少突胶质细胞谱系（目的1），以调查是否Shh信号调节谱系 皮质星形胶质细胞的特异性（目的2），并揭示潜在的分子 皮质RGC谱系转换的潜在机制（目的2和3）。我们将 结合联合收割机小鼠遗传学、MADM和交叉谱系分析、RNA-seq、单细胞RNA-seq、ChIP-seq、CUT&RUN、ATAC-seq和4C技术，实现这些 目标.

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.