Local regulation of neuronal microtubules and synaptic cargo

项目摘要 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。 人们越来越多地认识到，微管聚合物的性质，如它们的动力学或后动力学 翻译修饰，可以影响运动能力。也有充分证据表明，在神经元中，MT 轴突和树突之间的特性并不一致。然而，目前仍不清楚是什么机制导致了 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 这会影响到向突触的货物传递。它将通过研究一种非典型动蛋白VAB-8/KIF26的作用来做到这一点。 我们最近发现它是线虫体内微管组织和突触的局部调节因子。这个 这里提出的工作将决定(1)Wnt信号如何将VAB-8/KIF26的活性导向特定的轴突 (2)VAB-8/KIF26如何调节微管的长度和丰度，以及(3)这种调节如何 影响将货物运送到突触前部位。 回答这些问题将增加我们对神经元微管局部调控的基本理解 及其对轴突运输的影响。VAB-8/KIF26和Wnt信号的进化保守性 MTS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。

Project Summary 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.