? Astrocytes constitute more than half the number of cells in the central nervous system, and play numerous important roles in supporting the function of the CNS, including regulating the concentration of extracellular ions and neurotransmitters, forming brain blood barrier, regulating synapse formation and efficacy, inducing neurogenesis in the adult brain, and etc. In the injured CNS, astrocytes also have profound effects on the success or failure of reinnervation by regrowth of severed axons, as astrocytes participate in the formation of glial scars to impede axon regeneration. Despite the importance of astrocytes in the function and repairing of the CNS, the origin and molecular specification of astrocytes have remained mysterious. The long-term goal of this study is to understand the molecular mechanisms that control the specification and differentiation of astrocytes. Specifically, we plan to study the regulation and function of a candidate regulatory gene (Olig3) that may participate in the regulation of astrocyte development during embryogenesis. This regulatory gene is specifically expressed in subventricular cells outside the oligodendrogenic domain of embryonic spinal cord, and is hypothesized to promote astrocyte fate but inhibits oligodendrocyte development.
Two specific aims are proposed to test this hypothesis and to further investigate the molecular mechanisms underlying the specification and differentiation of astrocytes.
Specific aim 1 will investigate the role of Olig3 transcription factors in regulating astrocyte and oligodendrocyte development.
Specific aim 2 will study the regulation of Olig3 gene expression in the developing spinal cord. Results derived from the proposed studies will significantly enhance our understanding of the genetic circuitry governing the early specification and differentiation of astrocytes, and may provide theoretic basis for design of novel therapeutic approaches for prevention of glial scar formation in the injured spinal cord and promote regeneration of oligodendrocytes. ? ? ?
