MICROTUBULE DYNAMICS AND AXON GROWTH

微管动力学和轴突生长

• 批准号: 2267178
• 负责人: PETER W. BAAS
• 金额: $ 16.54万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2267178
• 关键词: axon; cellular polarity; centrosome; fluorescence microscopy; intracellular transport; laboratory rat; microinjections; microtubules; neurogenesis; neuronal transport; neutralizing antibody; polymerization; protein transport; tissue /cell culture; transmission electron microscopy; tubulin; vinblastine

Neurons extend axons over long distances to reach their target tissues during normal development and also during regeneration following injury. A growing body of evidence indicates that the growth and maintenance of the axon is dependent upon its cytoskeletal structure, and in particular of its microtubules. Microtubules are filamentous proteins that have important functions in generating and maintaining cellular architecture, regulating motile events in the cell, and in organizing the cytoplasm to carry out essential metabolic processes. Within the axon, microtubules are uniformly oriented with their "plus" ends distal to the cell body, and this organization is essential for directing organelle traffic in the axon. Unfortunately, the mechanisms by which the microtubule array of the axon is elaborated and organized are poorly understood, and a matter of some controversy. In particular, there has been disagreement with regard to the sites where axonal microtubules originate, and the relative contributions of microtubule assembly and transport to the growth of the axon. This application represents the continuation of efforts to address these questions. Recent indirect evidence suggests that axonal microtubules originate at the centrosome, and are then released for translocation into and down the axon. If this is correct, then there is a shift during transit from a large number of short microtubules to a smaller number of very long microtubules within the axon. With regard to the organization of these microtubules, an attractive possibility is that the translocation of microtubules through the cytoplasm occurs exclusively with plus-ends leading, thereby establishing the uniform polarity orientation of microtubules within the axon. In this application, experiments are proposed that will evaluate the role of the centrosome in generating axonal microtubules, and determine the relative contributions of microtubule transport and assembly to axon growth. Other experiments will specifically address whether the transport properties of axonal microtubules can account for their plus-end-distal polarity orientation. Finally, efforts will be directed toward measuring in very fine detail the lengths of individual microtubules throughout the axon. Collectively, the information derived from these studies will resolve important issues about axonal microtubules, and thereby provide new insights into the mechanisms by which the axonal microtubule array is elaborated and organized. Information of this kind is essential for understanding the cell biology of the neuron, and for elucidating the causes and potential cures for neuropathologies that involve axonal degeneration and/or retardation of axon growth.

神经元将轴突延伸很长的距离以到达目标组织 在正常发育期间以及受伤后的再生期间。 越来越多的证据表明，生长和维持 轴突取决于其细胞骨架结构，特别是 它的微管。微管是丝状蛋白质，具有 生成和维持细胞结构的重要功能， 调节细胞中的运动事件，并组织细胞质 进行必要的代谢过程。在轴突内，微管是 均匀定向，其“正”端远离细胞体，并且 该组织对于引导细胞器的运输至关重要 轴突。不幸的是，微管阵列的机制 轴突是精心设计和组织的，但人们对其知之甚少，并且问题在于 一些争议。尤其是在以下方面存在分歧： 到轴突微管起源的位点，以及相关的 微管组装和运输对生长的贡献 轴突。该应用程序代表了继续努力解决 这些问题。 最近的间接证据表明轴突微管起源于 中心体，然后被释放并易位到 轴突。如果这是正确的，那么在运输过程中就会有一个转变 大量的短微管到少量的长微管 轴突内的微管。关于这些活动的组织 微管中，一个有吸引力的可能性是易位 穿过细胞质的微管仅在正端发生 引导，从而建立统一的极性方向 轴突内的微管。在此应用中，实验是 提出将评估中心体在生成中的作用 轴突微管，并确定的相对贡献 微管运输和组装到轴突生长。其他实验将 特别解决轴突的运输特性是否 微管可以解释它们的正端-远端极性方向。 最后，我们将努力非常详细地衡量 整个轴突中各个微管的长度。总的来说， 从这些研究中获得的信息将解决有关的重要问题 轴突微管，从而提供对该机制的新见解 通过它精心设计和组织轴突微管阵列。 此类信息对于理解细胞生物学至关重要 神经元，并阐明其原因和潜在的治疗方法 涉及轴突变性和/或迟缓的神经病理学 轴突生长。