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Regulation of Axon Guidance by Second Messengers

第二信使对轴突引导的调节

基本信息

批准号：
8416996
负责人：
Timothy M Gomez
金额：
$ 30.72万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-20 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8416996
关键词：
Actins Adhesions Affect Axon Behavioral Biological Models Biological Neural Networks Biosensor Brain Brain-Derived Neurotrophic Factor Cell Adhesion Cell-Cell Adhesion Cells Chimeric Proteins Cognition Disorders Cues Cytoskeleton Data Defect Dendrites Detection Development Embryo Embryonic Development Environment Event Extracellular Matrix Extracellular Matrix Proteins Family member Fibroblasts Filopodia Focal Adhesion Kinase 1 Focal Adhesions Genes Growth Growth Cones Growth Factor Guanine Nucleotide Exchange Factors Health Human In Vitro Individual Integrins Knock-out Life Ligands Link Location Macromolecular Complexes Measures Membrane Mental Retardation Mental disorders Molecular Morphogenesis Mutation Nerve Nervous system structure Neurites Neuroglia Neurons Phosphotransferases Phosphotyrosine Process Proteins Regulation Research Role Second Messenger Systems Sensory Signal Transduction Signaling Protein Site Structure Synapses Testing Therapeutic Intervention Xenopus Zebrafish axon guidance base cell motility cognitive function design in vivo knock-down loss of function migration mutant nervous system development neurodevelopment oncoprotein p21 p21 activated kinase paxillin polymerization receptor response second messenger

项目摘要

DESCRIPTION (provided by applicant): The development of the nervous system requires the proper differentiation, migration and morphogenesis of neurons. The morphogenesis of individual neurons and the assembly of the trillions of neuronal connections that compose the human nervous system occurs through guided extension of axons and dendrites. The long-term objective of our research is to better understand the intracellular signaling cascades and effector mechanisms that are responsible for axon outgrowth and guidance in the developing brain. For this we must understand how nerve growth cones detect, integrate and respond to soluble, as well as cell- and substratum-associated guidance molecules in their environment. Mutations in genes involved in the detection and transduction of axon guidance information into directed neurite outgrowth are likely responsible for many deficits in cognitive function, including autisms, dyslexias, psychological disorders and mental retardations. Axon extension proceeds through a sequential process that involves leading edge membrane protrusion driven by actin polymerization, followed by adhesion and protrusion stabilization. New protrusions that do not adhere are retracted, as do existing protrusions that de-adhere. While extensive research has focused on the signals that control membrane protrusion and retraction, surprisingly little is known about the regulation of adhesion. Stabilization of growth cone protrusions to extracellular matrix (ECM) ligands occurs at specialized adhesion sites called point contacts. Point contacts are macromolecular complexes, containing both structure and signaling proteins, which link the cytoskeleton to the ECM through transmembrane integrin receptors. Our research is focused on understanding the molecular signaling events that control point contact assembly, maturation and disassembly and how axon guidance cues influence these processes to control axon pathfinding. Importantly, our evidence suggests that growth promoting axon guidance cues stimulate point contact assembly and turnover, while inhibitory cues slow the assembly of new point contacts and reduce turnover. We hypothesize that guidance of axons to their proper targets and stabilization of synaptic contacts requires modulation of integrin-dependent point contacts. We will test this hypothesis using a variety of approaches and model systems in three specific aims. In Aim 1, we will examine the role of Focal Adhesion Kinase (FAK) in the control of adhesion dynamics, veil protrusion and phosphotyrosine signaling at filopodial tips in response to axon guidance cues. In Aim 2, we will examine the role of p21-Activated Kinase (PAK) proteins in the regulation of integrin-dependent adhesion, cellular protrusion and axon outgrowth. Finally, in Aim 3, we will determine the role of adhesion site dynamics in axon guidance at several choice point in both Xenopus and zebrafish embryos.

描述（申请人提供）：神经系统的发育需要神经元的适当分化、迁移和形态发生。单个神经元的形态发生以及构成人类神经系统的数万亿个神经元连接的组装是通过轴突和树突的引导延伸而发生的。我们研究的长期目标是更好地了解细胞内信号级联和效应机制，这些机制负责轴突的生长和大脑发育中的引导。为此，我们必须了解神经生长锥如何检测、整合和响应环境中的可溶性以及细胞和基质相关的引导分子。与轴突引导信息的检测和转导相关的基因突变可能导致许多认知功能缺陷，包括自闭症、阅读障碍、心理障碍和精神发育迟滞。轴突延伸通过一个连续的过程进行，该过程涉及由肌动蛋白聚合驱动的前缘膜突出，然后是粘附和突出稳定。不粘附的新突出物会被缩回，现有的不粘附的突出物也会被缩回。虽然广泛的研究集中在控制膜突出和收缩的信号上，但令人惊讶的是，人们对粘附的调节知之甚少。生长锥突起对细胞外基质 (ECM) 配体的稳定发生在称为点接触的特殊粘附位点。点接触是大分子复合物，包含结构蛋白和信号蛋白，通过跨膜整合素受体将细胞骨架与 ECM 连接起来。我们的研究重点是了解控制点接触组装、成熟和分解的分子信号事件，以及轴突引导线索如何影响这些过程以控制轴突寻路。重要的是，我们的证据表明，促进生长的轴突引导信号刺激点接触组装和周转，而抑制信号则减缓新点接触的组装并减少周转。我们假设引导轴突到达适当的目标和稳定突触接触需要调节整合素依赖性点接触。我们将针对三个特定目标使用各种方法和模型系统来测试这一假设。在目标 1 中，我们将研究焦点粘附激酶 (FAK) 在控制粘附动力学、面纱突出和丝状伪足尖端磷酸酪氨酸信号传导以响应轴突引导线索中的作用。在目标 2 中，我们将研究 p21 激活激酶 (PAK) 蛋白在调节整合素依赖性粘附、细胞突出和轴突生长中的作用。最后，在目标 3 中，我们将确定非洲爪蟾和斑马鱼胚胎中几个选择点上粘附位点动力学在轴突引导中的作用。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Src-dependent tyrosine phosphorylation at the tips of growth cone filopodia promotes extension.

生长锥丝状伪足尖端的 Src 依赖性酪氨酸磷酸化促进延伸。

DOI：
10.1523/jneurosci.2680-05.2005
发表时间：
2005
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Robles,Estuardo;Woo,Stephanie;Gomez,TimothyM
通讯作者：
Gomez,TimothyM

Retinotopic mapping requires focal adhesion kinase-mediated regulation of growth cone adhesion.

DOI：
10.1523/jneurosci.4028-09.2009
发表时间：
2009-11-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Woo S;Rowan DJ;Gomez TM
通讯作者：
Gomez TM

Pioneering studies on the mechanisms of neuronal morphogenesis.

神经元形态发生机制的开创性研究。