Rho GTPase signaling in the developing cerebral cortex

项目摘要(请参阅实例)： 在皮质发育过程中，神经前体细胞增殖，然后离开脑室带(VZ)，定居在皮质板(CP)。这些未成熟细胞离开VZ后采取两种途径之一：1)沿着放射状胶质支架直接迁移到CP，以由内向外的方式定居；2)它们迁移到室下区(SVZ)，并呈现多极形态，成为中间祖细胞(IP)，在继续前往CP之前，经历另一轮细胞分裂。尽管已知这些事件的中断有助于儿科神经发育 紊乱，调节祖细胞在独特的神经源性利基中的保留和释放的因素还没有被很好地理解。小的RhoGTP酶，包括CDC42和RhoG，在发育中的皮质中作为祖细胞增殖和命运决定的调节因子。调节RhoGTP酶的机制，特别是在发育中的神经系统，还不是很清楚。这些调控因子由GEF和GAP组成)控制RhoGTP酶的GTP负载状态，从而控制RhoGTP酶的活性。由于GEF作为RhoGTPase的激活剂，我们假设GEF在RhoGTPase介导的大脑发育中的祖细胞增殖调节和命运决定中起关键作用。我们试图确定在发育中的大脑皮层的神经源性缝隙中有受限表达的GEF。我们的努力使我们找到了一种小鸟嘌呤交换因子(Sgef)，在神经发生的高峰期，它的表达仅限于VZ/SVZ。已知Sgef可诱导成纤维细胞和内皮细胞形成富含F-肌动蛋白的突起(1-2)。为了支持sgef在大脑皮层发育中的作用，sgef缺乏的小鼠表现出SVZ中神经前体细胞的增殖减少。我们将使用三个目标来验证我们的假设： 目的I：改变的环境生长因子表达是否能介导未成熟神经元行为的改变？ 目的II：GEF是否选择性地影响神经前体细胞的增殖和定位？ 目的III：上海世博会通过什么机制(S)调节发育中的大脑皮层？ 这些研究试图揭示GEF在哺乳动物大脑皮层发育中的机制和功能调节。通过关注Sgef，它的表达仅限于发育中的大脑皮层中定义的神经源性利基，其缺失似乎在中枢神经系统之外具有名义上的后果，我们能够利用发育中的大脑皮层作为模型来揭示GEF如何调节RhoGTPase信号的线索。‘

PROJECT SUMMARY (See Instnjctions): 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. '