Role of Olig3 gene in gliogenesis

描述(由申请人提供)： 星形胶质细胞占中枢神经系统细胞总数的一半以上，在支持中枢神经系统功能方面发挥着重要的作用，包括调节细胞外离子和神经递质的浓度，形成脑血屏障，调节突触的形成和疗效，诱导成年脑内的神经再生等。在受损的中枢神经系统中，星形胶质细胞还通过切断轴突的再生，对神经再生的成败有着深远的影响，因为星形胶质细胞参与了胶质瘢痕的形成，从而阻碍了轴突的再生。尽管星形胶质细胞在中枢神经系统的功能和修复中起着重要的作用，但星形胶质细胞的起源和分子特征一直是个谜。这项研究的长期目标是了解控制星形胶质细胞特化和分化的分子机制。具体地说，我们计划研究一个候选调控基因(Olig3)的调控和功能，该基因可能参与胚胎发育过程中星形胶质细胞发育的调控。这种调控基因在胚胎脊髓少突胶质细胞结构域之外的脑室下细胞中特异表达，并被认为促进星形胶质细胞的命运，但抑制少突胶质细胞的发育。提出了两个特定的目标来检验这一假说，并进一步研究星形胶质细胞特化和分化的分子机制。具体目的1：探讨寡核苷酸转录因子在调节星形胶质细胞和少突胶质细胞发育中的作用。具体目的2将研究寡核苷酸基因在脊髓发育过程中的表达调控。 这些研究结果将大大加深我们对星形胶质细胞早期特化和分化的遗传回路的理解，并可能为设计预防损伤脊髓胶质瘢痕形成和促进少突胶质细胞再生的新的治疗方法提供理论依据。

DESCRIPTION (provided by applicant): 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.