Local regulation of neuronal microtubules and synaptic cargo

神经元微管和突触货物的局部调节

基本信息

批准号：
10604300
负责人：
Shaul Yogev
金额：
$ 35.31万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604300
关键词：
Affect Animals Architecture Axon Axonal Transport Binding Biochemical Biological Caenorhabditis elegans Cells Clustered Regularly Interspaced Short Palindromic Repeats Cytoskeleton Data Defect Dendrites Disease Equilibrium Event Failure Functional disorder Genetic Genome engineering Health Image Immobilization In Vitro Kinesin Knowledge Length Link Maintenance Mediating Microtubule Polymerization Microtubules Molecular Molecular Motors Motor Neurons Outcome Pathway interactions Pattern Pharmacology Polymers Positioning Attribute Post-Translational Protein Processing Probability Property Publishing Regulation Role Signal Transduction Site Synapses Synaptic Vesicles Testing WNT Signaling Pathway Work cell motility extracellular genetic analysis in vivo in vivo imaging insight mutant neuron development pharmacologic presynaptic receptor reconstruction synaptogenesis ubiquitin-protein ligase

项目摘要

In neurons, microtubule polymers support axonal transport by molecular motors to deliver cargo to synapses. There is a growing understanding that the properties of microtubules polymers, such as their dynamics or post-translational modifications, can influence motor motility. There is also ample evidence that in neurons, MT properties are not uniform across axons and dendrites. However, it is still unclear what are the mechanisms that locally regulate neuronal microtubules, and how the resulting changes influence cargo transport. This proposal aims to understand how microtubule polymer length, abundance and distribution are locally regulated, and how this affects cargo delivery to synapses. It will do so by studying the role of an atypical kinesin, VAB-8/KIF26, which we recently identified as a local regulator of microtubule organization and synapses in C. elegans. The work proposed here will determine (1) how Wnt signaling directs the activity of VAB-8/KIF26 to a specific axonal sub-domain, (2) how VAB-8/KIF26 regulates microtubule length and abundance, and (3) how this regulation influences the delivery of cargo to presynaptic sites. Answering these questions will increase our basic understanding of local regulation of neuronal microtubules and its influence on axonal transport. The evolutionary conservation of VAB-8/KIF26 and Wnt signaling and the cardinal role of MTs in neuronal development, maintenance and dysfunction underscore the importance of this fundamental knowledge.

在神经元中，微管聚合物通过分子马达支持轴突运输，将货物运送到突触。人们越来越认识到微管聚合物的特性，例如其动力学或翻译后修饰，可以影响运动能力。还有充分的证据表明，在神经元中，MT 轴突和树突的特性并不统一。但目前尚不清楚其机制是什么局部调节神经元微管，以及由此产生的变化如何影响货物运输。这个提议旨在了解微管聚合物长度、丰度和分布是如何局部调节的，以及如何这会影响到突触的货物递送。它将通过研究非典型驱动蛋白 VAB-8/KIF26 的作用来实现这一目标，我们最近发现它是线虫微管组织和突触的局部调节因子。这这里提出的工作将确定 (1) Wnt 信号传导如何将 VAB-8/KIF26 的活性引导至特定的轴突子结构域，(2) VAB-8/KIF26 如何调节微管长度和丰度，以及 (3) 这种调节如何影响货物到突触前部位的输送。回答这些问题将增加我们对神经元微管局部调节的基本了解及其对轴突运输的影响。 VAB-8/KIF26 和 Wnt 信号传导的进化保守性及其 MT 在神经元发育、维持和功能障碍中的重要作用强调了这一点的重要性基础知识。