Molecular Control of Cortical Neural Stem Cells

描述（由申请人提供）：放射状胶质细胞在哺乳动物大脑皮质的构建中发挥着关键作用，首先在早期发育期间产生神经元，然后为神经元迁移提供指导，并在后期阶段产生星形胶质细胞。放射状胶质细胞发育、分化和神经元迁移的引导异常导致神经元的异常定位和连接。皮质放射状神经胶质细胞的决定是增殖、分化还是保持静止取决于多种信号机制的整合。Notch信号通路是发育中的大脑皮层中放射状胶质细胞建立和维持的关键调节因子。然而，Notch信号传导的特异性和背景依赖性的分子机制仍不清楚。在这项研究中，我们将调查的作用，一些分子介导的Notch依赖性调节放射状胶质细胞的功能。首先，我们将确定Delta-like 1和Jagged 1在调节放射状胶质细胞分化中的特异性和互补作用。其次，我们将表征Numb和Numb样，和E-钙粘蛋白在维持apicobasal极性的放射状胶质细胞之间的相互作用。最后，我们将描述振荡的机制和功能的Notch活动在皮层神经发生。我们将采用体外和体内系统，并使用功能丧失和获得技术来确定上述分子的功能和机制。阐明Notch信号传导和相关分子如何调节皮质放射状胶质细胞功能的分子机制，将促进对正常和异常脑发育以及干细胞生物学的理解。

DESCRIPTION (provided by applicant): Radial glial cells play a critical role in the construction of the mammalian cerebral cortex by first giving rise to neurons during early development, then providing guidance for neuronal migration, and at later stages, generating astrocytes. Abnormalities in radial glial development, differentiation, and guidance of neuronal migration lead to aberrant placement and connectivity of neurons. The decision of cortical radial glial cells to either multiply, differentiate or remain quiescent depends on an integration of multiple signaling mechanisms. The Notch signaling pathway is a key regulator of radial glial cell establishment and maintenance in the developing cerebral cortex. However, the molecular mechanisms underlying the specificity and context dependence of Notch signaling remain unclear. In this study, we will investigate the roles of a number of molecules in mediating Notch-dependent regulation of radial glial cell function. First, we will determine the specific and complementary roles of Delta-like 1 and Jagged 1 in regulating radial glial cell differentiation. Second, we will characterize putative interaction between Numb and Numb-like, and E-Cadherin in maintaining apicobasal polarity of radial glial cells. Finally, we will characterize the mechanism and function of oscillation in Notch activity during cortical neurogenesis. We will employ in vitro and in vivo systems and use both loss- and gain-of-function techniques to determine the functions and mechanisms of the above molecules. The elucidation of the molecular mechanisms of how Notch signaling and related molecules regulate cortical radial glial cell function as outlined in this proposal will advance the understanding of normal and abnormal brain development, and the stem cell biology.