Regulation of growth and pruning of neuronal arbors

项目描述（申请人提供）：本项目研究中枢神经系统神经元树突形态调控的分子机制。树突分支的结构决定了突触回路的布线和突触输入的整合。因此，神经元形态的控制和动态调节对于正常的神经系统功能至关重要。该项目的重点是一个名为α-chimaerin的基因，它可能是神经元形态发生的重要调节因子。两种α-嵌合蛋白同种型在发育中的神经系统中表达，其作为Rho-GTP酶的GTP酶激活蛋白发挥作用。本研究的目的是了解α-嵌合蛋白在小鼠神经元树状结构的形成和可塑性中的功能和调节。该项目采用生物化学，细胞生物学和解剖学方法相结合，以研究这些蛋白质在海马和小脑神经元中的功能。所提出的实验将首先检查α-嵌合蛋白功能的分子机制，在调节树突状乔木的形态（目的1）。随后，我们将研究α-嵌合蛋白是如何调节突触活动（目的2）。最后，我们将产生缺乏单个或多个a-嵌合蛋白同种型的突变小鼠，并分析体内树突和轴突的发育（目的3）。这些研究将探讨Rho-GTPases将神经元信号传导与细胞形态的动态调节联系起来的分子机制。这些机制可能与神经系统的正常发育有关，但也与成年生物体中神经元连接的可塑性有关。在药物滥用后观察到树突的结构改变。α-嵌合蛋白是与这种变化相关的良好候选因子，因为它们在功能上与成瘾中涉及的信号通路偶联。此外，已经提出α-嵌合蛋白的缺陷与自闭症和精神分裂症相关。因此，了解α-嵌合蛋白的细胞功能与人类健康高度相关。

DESCRIPTION (provided by applicant): This project investigates the molecular mechanisms that regulate the dendritic morphology of neurons in the central nervous system. The architecture of dendritic arborizations determines the wiring of synaptic circuits and the integration of synaptic inputs. Therefore, control and dynamic regulation of neuronal morphology are crucial for normal nervous system function. This project focuses on one gene named alpha-chimaerin that is likely to be an important regulator of neuronal morphogenesis. Two a-chimaerin isoforms are expressed in the developing nervous system that function as GTPase activating proteins for Rho-GTPases. It is the goal of this proposal to understand the function and regulation of a-chimaerins in the formation and plasticity of neuronal arbors in mice. The project employs a combination of biochemical, cell biological, and anatomical approaches to investigate the function of these proteins in hippocampal and cerebellar neurons. The proposed experiments will first examine the molecular mechanism of a-chimaerin function in regulating the morphology of dendritic arbors (Aim 1). Subsequently, we will investigate how a-chimaerin is regulated by synaptic activity (Aim 2). Finally, we will generate mutant mice lacking individual or multiple a-chimaerin isoforms and analyze the development of dendritic and axonal arbors in vivo (Aim 3). These studies will investigate a molecular mechanism that links neuronal signaling with the dynamic regulation of cell morphology by Rho-GTPases. These mechanisms are likely to be relevant for the normal development of the nervous system but also for the plasticity of neuronal connections in the adult organism. Structural alterations in dendrites are observed after drug abuse. Alpha-chimaerins are good candidate factors to be relevant for such changes since they are functionally coupled to signaling pathways implicated in addiction. Moreover, defects in a-chimaerins have been proposed to be associated with autism and schizophrenia. Understanding the cellular functions of a-chimaerins is therefore highly relevant for human health.