Molecular Mechanisms of Neuronal Morphogenesis

神经元形态发生的分子机制

• 批准号: 6399339
• 负责人: LIQUN LUO
• 金额: $ 31.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-25 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6399339
• 关键词: Drosophilidae; afferent nerve; animal genetic material tag; cell cycle proteins; chimeric proteins; developmental genetics; developmental neurobiology; enzyme activity; enzyme induction /repression; gene mutation; genetically modified animals; guanine nucleotide binding protein; intermolecular interaction; molecular cloning; neurogenesis; neurogenetics; neuronal guidance; protein kinase; site directed mutagenesis

DESCRIPTION (provided by applicant): The long-term goal of our research is to understand the molecular mechanisms by which neurons acquire their characteristic pattern of connectivity during development. Neurons are morphologically diverse cells that are specialized for communication with their elaborate dendrites designed to receive, and axons to send, information. These processes and the specificity by which they connect to each other define the functional nervous system. While recent work has demonstrated that directed growth of axons is determined by the extracellular cues, much is to be learned about how the growth cone interprets and translates these signals into fine reorganization of the cytoskeleton. Small GTP-binding proteins of the Rho subfamily, including Rho, Rac, and Cdc42, regulate the actin cytoskeleton from yeast to humans. We have previously shown that they play important and distinct roles in the morphogenesis of neurons in both flies and mammals. Our working hypothesis is that these GTP-binding proteins receive signals from cell surface receptors and in turn regulate reorganization of the cytoskeleton necessary for growth cone motility and guidance. We have recently established a genetic mosaic method to study the function of these ubiquitously expressed and pleiotropically functional genes in small populations of identified neurons in the Drosophila brain. In this application we propose to systematically investigate how Rho, Rac and Cdc42 regulate the neuronal cytoskeleton by studying genetic loss- and gain-of-function mutants in these Rho GTPases and their effector pathway components. We will also explore the potential "cross talk" between these downstream effector pathways. To investigate the functions of these genes, we will use several in vivo paradigms that we have characterized, in combination with in vitro cultures. Our studies will shed light on the role of each of the Rho GTPases, how they transduce signals to the cytoskeleton, and how these signal transduction pathways interact with each other to bring about the myriad of morphological changes regulated by the Rho GTPases. Mutations in the Rho GTPase signaling pathway components have been reported in many human diseases. These include human neurological diseases such as non-syndromic mental retardation and William's syndrome, underscoring the importance of these signaling molecules in the development and function of the nervous system, and in human mental health.

描述（由申请人提供）：我们研究的长期目标是 了解神经元获得其分子机制 开发过程中连通性的特征模式。神经元是 形态上多样的细胞，专门用于与其交流 精心设计的树突旨在接收和发送轴突。这些 过程及其相互连接的特异性定义 功能性神经系统。虽然最近的工作证明了指导 轴突的生长取决于细胞外提示，可以学习很多 关于生长锥如何解释并将这些信号转换为罚款 细胞骨架的重组。 Rho的小GTP结合蛋白 包括Rho，RAC和CDC42在内的亚家族调节肌动蛋白细胞骨架 酵母对人类。我们以前已经表明它们发挥着重要而独特的作用 在果蝇和哺乳动物中神经元的形态发生中的作用。我们的工作 假设是这些GTP结合蛋白从细胞表面接收信号 受体和受体调节细胞骨架的重组 生长锥运动和指导。 我们最近建立了一种遗传镶嵌方法来研究 这些无处不在的表达和多效性基因在小 果蝇大脑中鉴定出的神经元的种群。在此应用程序中 我们建议系统地研究RHO，RAC和CDC42如何调节 神经元细胞骨架通过研究遗传丧失和功能获得突变体 这些Rho GTPases及其效应途径成分。我们还将探索 这些下游效应器途径之间的潜在“交谈”。到 研究这些基因的功能，我们将使用几个体内范例 我们已经表征了体外培养物的特征。我们的研究 会阐明每个Rho GTPases的作用，它们如何转导 信号到细胞骨架，以及这些信号转导途径如何 相互互动以带来无数的形态变化 由Rho GTPases调节。 在Rho GTPase信号通路途径中的突变已经报道 许多人类疾病。这些包括人类神经疾病，例如 非混合性智力低下和威廉综合症，强调 这些信号分子在开发和功能中的重要性 神经系统和人类心理健康。