This project is focused on understanding the molecular and cellular mechanism underlying the generation of cell diversity with the CNS to achieve this goal we proposed to use two complementary approaches to examine neuro and gliogenesis within the telencephalon from the onset of neurogenesis, a time three days earlier than any previous study has examined. Second, we will use virally mediated ectopic expression as a means to study how the genes involved in neurogenesis act to control the decision of progenitors to differentiate or self-renew. What has made this approach possible is the use of high resolution ultrasound to guide injections into the telencephalic ventricles, as early as embryonic (E) day 9.5 of mouse development. Our lineage studies will focus on three specific questions. 1) When do regional boundaries act to limit clonal dispersion? 2) At what point are neuronal and glial lineages segregated during development? and 3) Are the populations of neurons contributing to primary neurogenesis derived from a segregated population of progenitors. We will complement these studies by investigating the molecular mechanisms underlying these cell fate decisions. Two molecular pathways, lateral signaling and genes controlling asymmetric cell division are candidates to control these processes. Specifically, we will examine the role of genes in the Notch signaling pathway, including Notch and Delta as well as the Numb and Numb-like which are thought to be involved in asymmetric cell divisions. In order to study the role of these genes we will use viral vectors to express wild type, dominant negative and activated forms of these molecules. The position, morphology and gene expression within clones resulting from control versus ectopic expression viral vector infections will allow us to evaluated the function of these genes during neural development.
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