Mechanisms of Axon Outgrowth and Targeting

轴突生长和靶向机制

基本信息

批准号：
7752480
负责人：
Deanna L Benson
金额：
$ 36.71万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-15 至 2011-12-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：在人脑中，超过200亿个神经元在发育过程中彼此之间彼此相互联系。尽管取得了重大进展，但在大多数情况下，这种情况如何仍然是一个谜。最近，我们发现细胞粘附分子L1可以直接与Ezrin，radixin和Moesin结合，这是将跨膜蛋白与肌动蛋白细胞骨架联系起来的ERM分子家族的成员。来自其他实验室的工作已经确定了L1在轴突束缚和指导中的重要性，我们的初步研究表明，ERM家族在将L1结合到生长生长中起着至关重要的作用。在非神经元细胞中的工作表明，小型GTPases的Rho家族的上游和下游的ERMS作用，并且ERM与结节性硬化症1基因产物Hamartin是Rho介导的粘附调节所必需的。这表明ERMS可能是神经分化和探路过程中肌动蛋白动力学的关键调节剂。拟议的工作的目的是定义神经元中ERM功能的性质，以解决如何响应神经突生长和底物的变化以及研究所涉及的信号通路，以动态调节ERMS。最初的研究将在可以密切控制环境的文化中进行。这项工作的结果将为轴突生长和分支调节中ERM功能的体内研究的分析和解释提供信息。