PLEXINS AND MOLECULAR MECHANISMS OF AXON GUIDANCE

描述（由申请人提供）：神经系统由复杂的神经元连接网络组成。在发育过程中形成适当的连接是建立功能性神经系统必不可少的第一步。本研究的总体目标是了解引导轴突找到合适靶点的分子机制。基因靶向技术、体外分子结合实验和体外神经元培养将用于研究轴突引导分子的特定功能作用。本课题的具体目的是：(1)通过分析丛蛋白敲除小鼠的轴突引导表型来研究丛蛋白的具体功能；(2)通过分析双敲除小鼠的表型和体外生化相互作用来表征丛蛋白的相互作用；(3)通过分析丛蛋白敲除小鼠的修剪表型和建立体外轴突分支修剪实验来探讨丛蛋白在刻板轴突修剪中的作用。这项研究将帮助我们了解轴突引导分子如何共同发挥作用，以确保在神经系统的发育过程中，初始神经元网络的形成过程中不会发生错误。更普遍的是，形成适当轴突连接的缺陷可能导致许多神经发育障碍，如自闭症、精神分裂症、联觉和智力迟钝。了解分子机制可以彻底改变我们对这些发育障碍的描述和治疗能力。

DESCRIPTION (provided by applicant): The nervous system consists of an intricate network of neuronal connections. The formation of proper connections during development is the essential first step in building a functional nervous system. The overall goal of this study is to understand the molecular mechanisms that guide axons to find their appropriate targets. Gene targeting techniques, in vitro molecular binding experiments, and in vitro neuronal cultures will be used to study specific functional role of axon guidance molecules. The specific aims of this proposal are: (1) to study the specific functions of plexins by analyzing the axon guidance phenotypes in plexin knockout mice, (2) to characterize the interactions of plexins by analyzing the phenotypes in double knockout mice and by studying the in vitro biochemical interactions, and (3) to explore the role of plexins in stereotyped axon pruning by analyzing the pruning phenotypes in plexin knockout mice and by establishing in vitro axonal branch pruning assays. This research will help us understand how axon guidance molecules function together to ensure that during the development of the nervous system no errors occur in the formation of the initial neuronal network. More generally, defects in forming appropriate axonal connections are likely to cause many neurodevelopmental disorders, such as autism, schizophrenia, synesthesia and mental retardation. Understanding the molecular mechanisms could revolutionize our ability to characterize and treat these developmental disorders.