Spatiotemporal mechanisms of in vivo axon initiation and targeting during development

项目摘要 神经系统调节动物行为和生理的许多方面，其功能依赖于 产生复杂的蜂窝连接网络。未能建立或维持适当的联系 可能会对健康产生深远的影响，包括智力和发育障碍，要求 存在强有力的发展机制，以确保其精确的组织。中的一个常见组织主题 神经系统是地形图，在地形图中神经元的空间关系在一个投影场 匹配目标字段的空间组织。通过利用光学、胚胎学和遗传学 斑马鱼的可及性，我们发现了一种新的地形图形成的时间机制 这不同于现有的“化学亲和力”模型，该模型涉及空间坐标的分子匹配。 迷走神经运动性轴突按顺序出现，前轴突比后轴突早几个小时出现 轴突。在头部周围平行的时间调节过程中，咽弓出现在 从前到后的出现顺序。然后长出的迷走神经轴突支配咽弓。 从前到后依次排列，形成了前神经元支配更多的地形图 前部靶点和后部神经元支配更多后部靶点。在本申请中，我建议 研究这两个平行的时间过程背后的分子机制。在《目标1》中我会 确定在体内轴突起始是如何在细胞水平上被调节的，并将识别差异 表达促进迷走神经前部神经元轴突发生和/或延缓后部神经元轴突发生的基因。在……里面 目的2研究运动神经元趋化因子肝细胞生长因子作为序列表达的作用。 迷走神经地形图所需的咽弓吸引剂。这项工作将建立新的 调节轴突指定和靶向的机制，并将阐明如何协调调节 时间发育事件可以指导体内复杂地形图的发展。

Project Summary The nervous system regulates many aspects of animal behavior and physiology, and its function relies on the generation of intricate networks of cellular connections. Failure to establish or maintain the proper connections can have profound health consequences, including intellectual and developmental disabilities, requiring that robust developmental mechanisms exist to ensure their precise organization. A common organizational motif in nervous systems is the topographic map, in which the spatial relationships of neurons in a projecting field matches the spatial organization of the target field. By leveraging the optical, embryological and genetic accessibility of the zebrafish, we have discovered a novel temporal mechanism of topographic map formation that is different from existing “chemoaffinity” models that involve the molecular matching of spatial coordinates. Vagus motor axons emerge sequentially, with anterior axons emerging several hours earlier than posterior axons. In a parallel temporally regulated process in the head periphery, pharyngeal arches appear in an anterior-to-posterior appearance sequence. The outgrowing vagus axons then innervate the pharyngeal arches sequentially from anterior to posterior, resulting in a topographic map in which anterior neurons innervate more anterior targets and posterior neurons innervate more posterior targets. In this application, I propose to investigate the molecular mechanisms underlying these two parallel temporal processes. In Aim 1 I will determine how axon initiation is regulated at the cellular level in vivo, and will identify the differentially expressed genes that promote axonogenesis in anterior vagus neurons and/or delay it in posterior neurons. In Aim 2 I will investigate the role of the motor neuron chemoattractant HGF as the sequentially expressed pharyngeal arch attractant that is required for vagus topographic mapping. This work will establish new mechanisms that regulate axon specification and targeting, and will elucidate how the coordinated regulation of temporal developmental events can guide the development of complex topographic maps in vivo.