Lineage Progression of Cortical Neural Stem Cells

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.

Grant Number: 5R01NS089777-10
NIH Institute/Center: NIH
Principal Investigator: Bin Chen