Local regulation of neuronal microtubules and synaptic cargo

神经元微管和突触货物的局部调节

• 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
• 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

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以将货物递送到突触。 越来越多的人认识到，微管聚合物的性质，如其动力学或翻译后修饰，可以影响运动。也有充分的证据表明，在神经元中，MT 在轴突和树突上的性质是不均匀的。然而，目前还不清楚是什么机制， 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。这项建议 旨在了解微管聚合物的长度，丰度和分布是如何局部调节的，以及如何 这影响了向突触的货物递送。它将通过研究一种非典型驱动蛋白VAB-8/KIF 26的作用来实现， 我们最近发现它是C.优美的的 本文提出的工作将确定（1）Wnt信号传导如何将VAB-8/KIF 26的活性导向特定的轴突 亚结构域，（2）VAB-8/KIF 26如何调节微管长度和丰度，以及（3）这种调节如何 影响到突触前部位的运输。 对这些问题的探讨将增加我们对神经元微管局部调节的基本认识 及其对轴突运输的影响。VAB-8/KIF 26和Wnt信号转导的进化保守性以及VAB-8/KIF 26和Wnt信号转导的分子机制 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。