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的分子调控机制。树突分支的结构决定了突触电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神经系统的正常功能至关重要。这个项目的重点是一个名为α -嵌合蛋白的基因，它可能是神经元形态发生的重要调节因子。两种a-嵌合蛋白异构体在发育中的神经系统中表达，作为rho -GTPase的GTPase激活蛋白。本文旨在了解a-嵌合蛋白在小鼠神经元乔木形成和可塑性中的作用和调控。该项目采用生物化学、细胞生物学和解剖学相结合的方法来研究这些蛋白质在海马和小脑神经元中的功能。拟进行的实验将首先研究a-嵌合蛋白调节树突乔木形态的分子机制（目的1）。随后，我们将研究a-嵌合蛋白是如何通过突触活动调节的（目的2）。最后，我们将产生缺乏单个或多个a-嵌合蛋白亚型的突变小鼠，并分析体内树突和轴突乔木的发育（目的3）。这些研究将探讨Rho-GTPases对细胞形态的动态调控与神经元信号传导之间的分子机制。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。药物滥用后树突结构发生改变。α -嵌合蛋白是与这些变化相关的良好候选因子，因为它们在功能上与成瘾相关的信号通路耦合。此外，a-嵌合蛋白的缺陷被认为与自闭症和精神分裂症有关。因此，了解a-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.