Spatiotemporal mechanisms of in vivo axon initiation and targeting during development

发育过程中体内轴突起始和靶向的时空机制

• 批准号: 9771303
• 负责人: Adam James Isabella
• 金额: $ 6.74万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9771303
• 关键词: Animal Behavior; Anterior; Appearance; Axon; Branchial arch structure; Cell membrane; Cells; Chemotactic Factors; Complex; Cues; Deglutition; Development; Digestion; Embryonic Development; Embryonic Structures; Enhancers; Ensure; Event; Failure; Generations; Genes; Genetic; Growth; Head; Health; Heart Rate; Hour; Image; In Situ Hybridization; Intellectual functioning disability; Label; Learning; Ligands; Maps; Modeling; Molecular; Molecular Profiling; Morphology; Mosaicism; Motor; Motor Neurons; Mutagenesis; Nervous system structure; Neurons; Optics; Pattern; Pharmacology; Physiological; Physiology; Population; Process; Proteins; Proto-Oncogenes; Regulation; Resolution; Role; Signal Transduction; Speech; System; Testing; Time; Tissues; Transgenic Organisms; Vagus nerve structure; Visceral; Work; Zebrafish; differential expression; in vivo; insight; nerve supply; novel; receptor; receptor expression; spatial relationship; spatiotemporal; transcriptome sequencing; virtual

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.

项目摘要 神经系统调节动物行为和生理的许多方面，并且其功能依赖于神经系统。 复杂的细胞连接网络的产生。未能建立或维持适当的连接 可能会对健康产生深远的影响，包括智力和发育障碍， 存在着强有力的发展机制，以确保其精确的组织。一个共同的组织主题， 神经系统是一幅地形图，其中神经元在投影场中的空间关系 匹配目标字段的空间组织。通过利用光学胚胎学和遗传学 斑马鱼的可访问性，我们发现了一种新的地形图形成的时间机制 这与现有的涉及空间坐标的分子匹配的“化学亲和性”模型不同。 迷走神经运动轴突顺序出现，前轴突比后轴突早几个小时出现 轴突在头部周边的平行时间调节过程中，咽弓出现在 前-后外观顺序。长出的迷走神经轴突支配咽弓 从前部到后部顺序排列，导致一个地形图，其中前部神经元支配更多 前靶和后神经元支配更多的后靶。在本申请中，本人建议 研究这两个平行时间过程的分子机制。目标1我会 确定轴突起始是如何在体内细胞水平上调节的，并将识别差异 表达促进前迷走神经元中的轴突发生和/或延迟后迷走神经元中的轴突发生的基因。在 目的2探讨运动神经元趋化因子HGF在运动神经元表达中的作用。 迷走神经地形图绘制所需的咽弓吸引剂。这项工作将建立新的 机制，调节轴突规格和靶向，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育。