Signaling Mechanisms Regulating Rac-dependent Synaptic and Dendritic Development

调节 Rac 依赖性突触和树突发育的信号机制

基本信息

批准号：
8289540
负责人：
Kimberly R Tolias
金额：
$ 32.91万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8289540
关键词：
Actins Address Adhesions Affect Behavioral Biochemical Biological Assay Biotinylation Bipolar Disorder Boxing Brain Brain Diseases Cadherins Cell Adhesion Cell Adhesion Molecules Cells Cognition Disorders Complex Dendrites Dendritic Spines Development Ephrin B Receptor Excitatory Synapse Family Fluorescence Resonance Energy Transfer Genetic Transcription Growth Growth and Development function Guanosine Triphosphate Phosphohydrolases Health Human Image Imaging Techniques Immunofluorescence Immunologic In Vitro Knock-out Knockout Mice Learning Link Maintenance Mediating Memory Mental Retardation Molecular Morphogenesis Mutate N-Cadherin N-Methyl-D-Aspartate Receptors Nervous system structure Neurons Play Process Protein Biosynthesis Proteins RNA Interference Receptor Activation Regulation Resolution Role Signal Pathway Signal Transduction Site Surface Synapses Synaptic Receptors Syndrome Techniques Testing Vertebral column density design in vivo Model inhibitor/antagonist insight member mutant nervous system development overexpression receptor coupling research study rho rho GTP-Binding Proteins spatiotemporal trafficking

项目摘要

DESCRIPTION (provided by applicant): Formation of a functional nervous system requires the proper development and remodeling of dendrites and dendritic spines, the primary sites of excitatory synapses in the brain. Rho family GTPases play critical roles in regulating these processes. In particular, the Rho GTPase Rac promotes dendritic arborization and the formation and maintenance of spines. Precise spatio-temporal regulation of Rac activity is essential for its function, since aberrant Rac signaling results in dendrite and spine abnormalities and cognitive disorders including mental retardation. Despite its importance, the mechanisms that regulate Rac signaling in neurons remain poorly understood. We previously identified the Rac-specific activator Tiam1 as a critical regulator of dendrite, spine, and synapse development. We demonstrated that Tiam1 mediates both NMDA receptor- and EphB receptor-dependent spine development by coupling these receptors to Rac signaling pathways that control actin cytoskeletal remodeling and protein synthesis. Recently, we have also identified the Rac-specific inhibitor Bcr as a Tiam1-interacting protein that blocks Tiam1-induced Rac activation and actin remodeling. Overexpression and knockout experiments indicate that Bcr restricts the formation and growth of spines and dendrites. The complex between Tiam1 and Bcr may serve as an "on-off switch" for precisely regulating Rac signaling in neurons, which is essential for the proper formation and remodeling of spines, synapses, and dendrites. To test this hypothesis, we propose the following specific aims: 1) to determine the role of Bcr in restricting synapse development and dendritic growth; 2) to identify the mechanisms by which EphB and NMDA receptors regulate the Tiam1-Bcr complex, and determine the consequences on Rac activation and synapse development; and 3) to elucidate the role of the Tiam1-Bcr complex in regulating N-cadherin-mediated synaptic adhesion. To address these questions, we will use a multifaceted approach employing a combination of molecular, cellular, biochemical, and high-resolution imaging techniques. Results from the proposed studies will provide critical insight into the fundamental mechanisms that regulate Rac activation and Rac-dependent synaptic and dendritic development in neurons, and help to elucidate how disruptions in Rac GTPase signaling give rise to cognitive disorders such as mental retardation. PUBLIC HEALTH RELEVANCE: We propose to investigate the mechanisms that regulate how connections in the brain (synapses) form during development and how they remodeling during processes like learning and memory. We are studying a particular signaling pathway that causes mental retardation when mutated in humans. Results from our studies should provide new insight into the fundamental mechanisms of brain development and memory formation, and should enhance our understanding of how disruptions in these processes give rise to brain disorders such as mental retardation.

描述（由申请人提供）：功能性神经系统的形成需要对树突和树突状棘的适当发展和重塑，这是大脑中兴奋性突触的主要部位。 Rho Family GTPases在调节这些过程中起关键作用。特别是，Rho GTPase RAC促进了树突状树博化以及刺的形成和维护。 RAC活性的精确时空调节对于其功能至关重要，因为异常的RAC信号导致树突和脊柱异常和包括智力低下的认知障碍。尽管它的重要性，但调节神经元中RAC信号的机制仍然很少理解。我们以前以前将RAC特异性激活剂TIAM1确定为木霉，脊柱和突触发育的关键调节剂。我们证明TIAM1通过将这些受体与控制肌动蛋白细胞骨架重塑和蛋白质合成的RAC信号通路偶联来介导NMDA受体和EPHB受体依赖性脊柱发育。最近，我们还确定了RAC特异性抑制剂BCR是TIAM1相互作用的蛋白质，可阻断TiAM1诱导的RAC激活和肌动蛋白的重塑。过表达和敲除实验表明，BCR限制了刺和树突的形成和生长。 TIAM1和BCR之间的复合物可以用作精确调节神经元中RAC信号的“开关开关”，这对于刺，突触和树突的正确形成和重塑至关重要。为了检验这一假设，我们提出以下特定目的：1）确定BCR在限制突触发展和树突生长中的作用； 2）确定EPHB和NMDA受体调节TIAM1-BCR复合物的机制，并确定对RAC激活和突触发展的后果； 3）阐明TiAM1-BCR复合物在调节N-钙粘蛋白介导的突触粘附方面的作用。为了解决这些问题，我们将采用一种多面方法，使用分子，细胞，生化和高分辨率成像技术的组合。拟议的研究的结果将提供对调节RAC激活和RAC依赖性突触和树突发展的基本机制的重要见解，并有助于阐明RAC GTPase信号的破坏如何引起诸如智力障碍之类的认知障碍。公共卫生相关性：我们建议研究调节开发过程中大脑中连接（突触）形式的机制，以及它们在学习和记忆等过程中的重塑。我们正在研究一种特定的信号传导途径，该途径在人类中突变时会导致智力低下。我们的研究结果应提供对大脑发育和记忆形成的基本机制的新见解，并应增强我们对这些过程中的破坏如何引起脑部疾病（例如智力障碍）的理解。