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

基本信息

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
项目类别：
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

项目摘要

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.

项目概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。无法建立或维持正确的连接。可能会产生深远的健康后果，包括智力和发育障碍，因此需要存在强大的发展机制以确保其精确组织共同的组织主题。神经系统是地形图，其中神经元在投影场中的空间关系通过利用光学、胚胎学和遗传学来匹配目标区域的空间组织。斑马鱼的可及性，我们发现了地形图形成的一种新的时间机制这与现有的涉及空间坐标分子匹配的“化学亲和”模型不同。迷走运动轴突依次出现，前轴突比后轴突早几个小时出现在头部周边的一个平行的时间调节过程中，咽弓出现在一个轴突中。然后，向外生长的迷走神经轴突支配咽弓。按顺序从前到后，产生一个地形图，其中前神经元支配更多在此应用中，前部目标和后部神经元支配更多后部目标。在目标 1 中，我将研究这两个并行时间过程背后的分子机制。确定如何在体内细胞水平上调节轴突起始，并识别差异表达促进前迷走神经元轴突发生和/或延迟后神经元轴突发生的基因。目标 2 我将研究运动神经元趋化剂 HGF 作为顺序表达的作用这项工作将建立新的迷走神经地形图所需的咽弓引诱剂。调节轴突规范和靶向的机制，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育。