During cortical development, neuronal progenitors proliferate and then migrate away from the ventricular zone (VZ) to take up residence in the cortical plate (CP). These immature cells take one of two paths upon exiting the VZ: 1) migrating directly along the radial glia scaffold to the CP, taking up residence in an inside out fashion or 2) they migrate to the subventricular zone (SVZ) and take on a multipolar morphology to become intermediate progenitors (IPs), undergo an additional round of cell division before continuing on their way to the CP. Although disruption in these events are known to contribute to pediatric neurodevelopmental disorders, the factors regulating progenitor retention in, and release from, unique neurogenic niches are not well understood. Small RhoGTPases, including cdc42 and RhoG, serve as regulators of progenitor proliferation and fate determination within the developing cortex. The mechanisms regulating RhoGTPases particularly in the developing nervous system, are not well understood. These regulators, comprised of GEFs and GAP) control the GTP-loading state, and thus activity, of RhoGTPases. Because GEFs act as activators for RhoGTPase, we hypothesize that GEFs are critical to RhoGTPase-mediated regulation of progenitor proliferation and fate determination in the developing cerebral cortex. We sought to identify GEFs with restricted expression in neurogenic niches of the developing cerebral cortex. Our efforts led us to a small guanine exchange factor (SGEF) whose expression is restricted to the VZ/SVZ during the peak of neurogenesis. SGEF is known to induce formation of F-actin rich protrusions on fibroblasts and endothelial cells (1-2). In support of a role for SGEF in the developing cerebral cortex, mice deficient in SGEF {SGEF^') exhibit reduced neural progenitor proliferation in the SVZ. We will use three aims to test our hypothesis:
Aim I : Can altered GEF expression mediate changes in the behavior of immature neurons? Aim II: Do GEFs selectively influence the proliferation and placement of neural progenitors? Aim III: By what mechanism(s) does SGEF regulate the developing cerebral cortex? These studies seek to uncover the mechanism and functional regulation of GEFs in the development of the mammalian cerebral cortex. By focusing on SGEF, whose expression is restricted to a defined neurogenic niche in the developing cerebral cortex and whose deletion appears to have nominal consequences outside of the central nervous system, we are able to use the developing cerebral cortex as a model to uncover clues about how GEFs function to regulate RhoGTPase signaling. '
By defining these basic mechanisms of RhoGTPase regulation in the developing nervous system, we will provide crucial insight into neurodevelopment. Furthermore, by defining the mechanisms responsible for regulating neural progenitor proliferation, we might be able to manipulate these GEF-dependent processes in neuropediatric or neurodegenerative diseases to activate neuronal proliferation and differentiation.
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