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，其功能依赖于 生成复杂的细胞连接网络。无法建立或维护正确的连接 可以产生深远的健康后果，包括智力和发展障碍，要求 存在强大的发展机制，以确保其确切的组织。一个共同的组织主题 神经系统是地形图，其中神经元在投影领域的空间关系 匹配目标字段的空间组织。通过利用光学，胚胎学和遗传 斑马鱼的可访问性，我们发现了一个新颖的地形图形成临时机制 这与涉及空间坐标的分子匹配的现有“化学亲和力”模型不同。 迷走轴运动轴突依次出现，前轴突比后部出现了几个小时 轴突。在头部外围的暂时调节过程中，咽弓出现在一个 前到后方的外观序列。然后，超越的迷走轴突支配了咽弓 依次从前到后，产生地形图，其中前神经元更多地支配 前靶和后神经元支配更多的后靶靶标。在此应用程序中，我建议 研究这两个平行临时过程的基础分子机制。在目标1中我会 确定如何在体内调节轴突计划在细胞水平上的调节，并将识别出不同的识别 表达的基因促进前迷走神经元中轴突发生和/或在后神经元中延迟其。在 AIM 2我将研究运动神经元趋化剂HGF的作用，因为依次表达 迷走形地图所需的咽弓吸引剂。这项工作将建立新的 调节轴突规范和靶向的机制，并将阐明如何协调调节 临时发展事件可以指导体内复杂的地形图的发展。