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，在很大程度上仍是一个谜。最近，我们发现细胞粘附分子L1可以直接结合ezrin， radixin和moesin，这些分子是ERM家族的成员，将跨膜蛋白连接到肌动蛋白细胞骨架。其他实验室的工作已经确定了L1在轴突束化和引导中的重要性，我们的初步研究表明，ERM家族在将L1结合转化为生长过程中起着关键作用。在非神经元细胞中的研究表明，ERM同时作用于Rho小gtpase家族的上游和下游，并且ERM与结节性硬化症1基因产物错构体的结合是Rho介导的粘附调节所必需的。这表明erm可能是神经分化和寻径过程中肌动蛋白动力学的关键调节因子。本研究的目标是定义神经元中ERM功能的本质，解决ERM是如何响应神经突生长的特定阶段和底物的变化而动态调节的，并研究所涉及的信号通路。最初的研究将在环境可以严格控制的文化中进行。这项工作的结果将为ERM功能在轴突生长和分支调节中的体内研究提供分析和解释。

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.