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: 10379926
• 负责人: Shaul Yogev
• 金额: $ 36.56万
• 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/10379926
• 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; In Vitro; Kinesin; Knowledge; Length; Link; Maintenance; Mediating; 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; Testing; Vesicle; WNT Signaling Pathway; Work; base; cell motility; extracellular; genetic analysis; in vivo; in vivo imaging; insight; mutant; neuron development; 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，将货物运送到突触。