Mechanisms of Axon Outgrowth and Targeting

描述（由申请人提供）：在人类大脑中，超过200亿个神经元在发育过程中彼此精确连接。尽管取得了重大进展，但这是如何发生的，在很大程度上仍然是一个谜。最近，我们已经发现，细胞粘附分子L1可以直接结合到ezrin，radixin和膜突蛋白，连接跨膜蛋白的肌动蛋白细胞骨架的分子的ERM家族的成员。其他实验室的工作已经确立了L1在轴突成束和指导中的重要性，我们的初步研究表明，ERM家族在将L1结合转化为产物中起着关键作用。在非神经元细胞中的工作表明，ERMs作用于Rho家族的小GTP酶的上游和下游，并且ERMs与结节性硬化症1基因产物错构蛋白的结合是Rho介导的粘附调节所需的。这表明ERMs可能是神经分化和寻路过程中肌动蛋白动力学的关键调节因子。拟议的工作的目标是定义神经元中的ERM功能的性质，以解决如何ERMs动态调节响应特定阶段的神经突生长和底物的变化，并调查所涉及的信号通路。最初的研究将在环境可以严格控制的培养物中进行。从这项工作的结果将告知ERM功能的轴突生长和分支的调节在体内研究的分析和解释。

DESCRIPTION (provided by applicant): In the human brain more than 20 billion neurons become precisely connected to one another during development. How this happens, despite significant advances, remains for the most part, a mystery. Recently, we have found that the cell adhesion molecule L1 can bind directly to ezrin, radixin and moesin, members of the ERM family of molecules that link transmembrane proteins to the actin cytoskeleton. Work from other laboratories has established the importance of L1 in axon fasciculation and guidance, and our preliminary studies indicate that the ERM family plays a critical role in translating L1 binding into outgrowth. Work in non-neuronal cells suggests that ERMs act both upstream and downstream of the Rho family of small GTPases and that ERM binding to the tuberous sclerosis1 gene product, hamartin, is required for Rho mediated regulation of adhesion. This suggests that ERMs may be key regulators of actin dynamics during neural differentiation and pathfinding. The goal of the proposed work is to define the nature of ERM function in neurons, to address how ERMs are dynamically regulated in response to particular phases of neurite outgrowth and to changes in substrate, and to investigate the signaling pathways involved. The initial studies will be carried out in culture where environment can be closely controlled. Results from this work will inform the analysis and interpretation of an in vivo study of ERM function in the regulation of axon outgrowth and branching.