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.
