Molecular mechanisms of dendrite development in mammalian CNS

哺乳动物中枢神经系统树突发育的分子机制

基本信息

批准号：
8011342
负责人：
YUH NUNG JAN
金额：
$ 33.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011342
关键词：
Ablation Adopted Affect Area Autistic Disorder Axon Biological Biological Models Cells Cellular biology Defect Dendrites Development Developmental Process Diagnosis Dissection Drosophila genus Employee Strikes Exhibits Future Genes Genetic Genetic Screening Genetic Techniques Goals Golgi Apparatus Health Hippocampus (Brain)Homologous Gene Human Knock-out Lasers Lead Mammals Membrane Mental disorders Methods Molecular Morphogenesis Movement Mutation Names Nervous system structure Neuraxis Neurons Pathology Pathway interactions Pattern Peripheral Nervous System Positioning Attribute Presynaptic Terminals Quantum Dots Rattus Reporter Research Role Secretory Component Small Interfering RNA System Tamoxifen Techniques Testing Time Work axon growth axon guidance base gene function in vivo insight interest knockout gene loss of function mutant nervous system disorder novel programs recombinase success tool trafficking

项目摘要

DESCRIPTION (provided by applicant): For a nervous system to be properly wired, the axons have to be guided toward the correct targets and the dendrites need to have the correct branching pattern and structural specialization. At present, much less is known about the molecular mechanisms that control dendrite development as compared to those controlling axon guidance. A few years ago, our lab initiated a very fruitful genetic dissection of dendrite development using Drosophila Multiple Dendritic neurons as a model system. This ongoing genetic screen has begun to yield important insights about the molecular basis of dendrite development in Drosophila. Given the striking conservation of many molecular mechanisms that control various developmental processes including axon guidance, it is highly likely that many of the molecular mechanisms controlling dendrite development are conserved between Drosophila and mammals. Indeed, we already have considerable success in our ongoing efforts to extend our findings from Drosophila to mammalian CNS. We propose to focus on the group of dar (dendritic arborization reduction) genes. Mutations of any of the dar genes lead to defective dendrtic arbor but normal axonal projections. Thus, studies of dar genes should reveal how axons and dendrites are made differently, which is of fundamental importance in understanding dendrite development. From our mutant screen, we estimate that there may be a total of about 20 dar genes in Drosophila. Of the 5 dar genes that we have cloned so far, all five have mammalian homologues. Remarkably, 3 encode components of the secretory pathway. These results reveal the preferential role of ER-Golgi trafficking and Golgi outposts in dendrite arborization. In two test cases, both mammalian homologues have dendrite specific developmental function. Thus, we believe the Dar genes will be instrumental in revealing evolutionarily conserved mechanisms in regulating dendrite but not axon morphogenesis. We propose to systematically identify mammalian homologues of Drosophila dar genes. We will use cell biological and genetic techniques to study the function of mammalian Dar genes in cultured rat hippocampal neurons with the emphasis on the role of ER/Golgi trafficking and Golgi outposts in dendrite development. Additionally, we will study the in vivo roles of the most interesting Dar genes in dendrte development of mammalian CNS by using our newly developed method to knockout genes in a spatially and temporally controlled manner. This work will contribute to the understanding and eventual treatment of human neurological diseases many of which have pathology in dendrites. PUBLIC HEALTH RELEVANCE: This project aims to unravel the molecular mechanisms that control dendrite development in mammalian central nervous system. Given that dendrite defects are the likely cause of many mental disorders such as autism, this project could contribute to the diagnosis and possible treatment in the future.

描述（由申请人提供）：为了使神经系统正确连接，轴突必须被引导向正确的目标，树突需要具有正确的分支模式和结构专门化。目前，与控制轴突引导的分子机制相比，人们对控制树突发育的分子机制知之甚少。几年前，我们的实验室使用果蝇多树突神经元作为模型系统，对树突发育进行了非常富有成效的遗传解剖。这种正在进行的遗传筛选已经开始对果蝇树突发育的分子基础产生重要的见解。鉴于控制各种发育过程（包括轴突引导）的许多分子机制的显着保守性，控制树突发育的许多分子机制很可能在果蝇和哺乳动物之间是保守的。事实上，我们不断努力将我们的发现从果蝇扩展到哺乳动物中枢神经系统，已经取得了相当大的成功。我们建议重点关注 dar（树突分枝减少）基因组。任何 dar 基因的突变都会导致树突乔木有缺陷，但轴突投射正常。因此，对 dar 基因的研究应该揭示轴突和树突的不同形成方式，这对于理解树突发育至关重要。根据我们的突变筛选，我们估计果蝇中可能总共有大约 20 个 dar 基因。迄今为止我们克隆的 5 个 dar 基因中，所有 5 个基因都具有哺乳动物同源物。值得注意的是，3 编码分泌途径的成分。这些结果揭示了内质网-高尔基体运输和高尔基体前哨在树突分枝中的优先作用。在两个测试案例中，两种哺乳动物同源物都具有树突特异性发育功能。因此，我们相信 Dar 基因将有助于揭示调节树突而非轴突形态发生的进化保守机制。我们建议系统地鉴定果蝇 dar 基因的哺乳动物同源物。我们将使用细胞生物学和遗传技术来研究哺乳动物 Dar 基因在培养的大鼠海马神经元中的功能，重点是 ER/高尔基体运输和高尔基体前哨在树突发育中的作用。此外，我们将通过使用我们新开发的方法以空间和时间控制的方式敲除基因，研究最有趣的 Dar 基因在哺乳动物中枢神经系统树突发育中的体内作用。这项工作将有助于理解和最终治疗人类神经系统疾病，其中许多疾病在树突中存在病理学。公共健康相关性：该项目旨在揭示控制哺乳动物中枢神经系统树突发育的分子机制。鉴于树突缺陷可能是导致自闭症等许多精神疾病的原因，该项目可能有助于未来的诊断和可能的治疗。