Mechanisms of Axon Outgrowth and Targeting

描述(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相互精确连接。尽管取得了重大进展，但这种情况是如何发生的，在很大程度上仍然是一个谜。最近，我们发现细胞黏附分子L1可以直接与ERM家族中连接跨膜蛋白和肌动蛋白细胞骨架的分子Ezrin、Radioxin和Moesin结合。其他实验室的工作已经证实了L1在轴突震颤和引导中的重要性，我们的初步研究表明，ERM家族在将L1结合转化为副产物的过程中发挥着关键作用。在非神经细胞中的研究表明，ERM既作用于Rho家族小GTP酶的上游，也作用于Rho家族的下游，并且ERM与结节硬化症1基因产物hamartin的结合是Rho介导黏附调节所必需的。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。这项拟议工作的目的是确定神经元ERM功能的性质，解决ERM是如何随着轴突生长的特定阶段和底物的变化而动态调节的，并研究涉及的信号通路。最初的研究将在环境可以严密控制的培养环境中进行。这项工作的结果将为分析和解释ERM在调节轴突生长和分支中的体内研究提供信息。

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.