A wealth of data suggest that aberrations in Notch signaling in humans results in a host of development brain disorders, such as CADASIL disease. This grant examines the functions of Notch signaling during neurogenesis in the telencephalon, using a combined gain of function/loss of function approach. We hypothesize that Notch function can be divided into distinct early and late roles. We believe that the function of Notch signaling during early neurogenesis is to maintain progenitors in an undifferentiated state. By contrast, in late telencephalic development, we believe Notch signaling functions to determine neuronal versus glial identity. To test the first part of this model, we will examine the consequences of perturbing Notch signaling in the early embryo by systematically removing the different Notch receptors or by conditional ablation of RBP, an obligate downstream effector required for Notch signaling. To look at the later roles of Notch signaling, we will use both transgenic and virally-mediated methods for modulating Notch signaling both globally and mosiacally within the telencephalon. We will thus directly test in late neurogenesis whether changes in Notch signaling result in progenitors being biased to a neuronal or glial identity. Furthermore, to examine whether Notch function during this period of telencephalic development is acting in an instructive or permissive manner, we have designed an approach to transiently activate Notch signaling, to see if this abrogates telencephalic progenitors' ability to adopt a neuronal identity when shifted to in vivo or in vitro to neurogenic environments. These studies will provide an accurate accounting of the function of Notch signaling both temporally and spatially within the developing telencephalon. By determining the consequences of Notch signaling in different developmental consequences, this study will determine whether qualitative as well as quantitative changes in the requirement for Notch signaling occur at various time points of development. Furthermore, given recent evidence that Notch function plays a central role in maintaining CNS stem cells and acts in determining cell fates, better understanding the role of this pathway in normal development will provide clues as to how patterning and neurogenesis are coordinated and open the way to the development of rational cell replacement therapies.
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