Developmental mechanisms specifying vagal innervation of organ targets

项目摘要/摘要： 在发育过程中，中枢神经系统与身体建立精确的联系，以 协调器官功能。大脑和身体之间这种交流的一个重要组成部分是迷走神经 神经(脑神经X)，支配包括心脏、肺和消化道在内的多个器官系统 调节血压、心率、呼吸和消化。尽管扮演着重要的角色，但分子 引导迷走神经到达这些器官靶点的机制仍然完全不清楚。我们已经开发出 斑马鱼胚胎作为询问迷走神经发育的强大模型，利用其 光学清晰度和遗传可及性。迷走神经由两个上升的感觉纤维组成，这些纤维 向大脑传递器官状态，以及向器官传递相互运动命令的下行运动投射。 迷走神经也以头部咽弓派生的肌肉为靶点，莫恩斯实验室此前曾 描述了运动神经元在大脑中的位置与它们在大脑中的靶点之间的拓扑关系 Head，并发现了这张地图发展的时空机制。初步数据 我在这里展示了迷走神经对器官的投射也是按地形图组织的，其中 支配不同器官(心脏、胃、肠)的迷走运动神经元在空间上被分隔在 后脑迷走神经核。我还观察到迷走神经运动投射到达内脏的时间比他们的 感官对应的，这让我假设内脏需要正确的运动神经支配 随后的感觉神经支配。在这里，我建议通过以下目标来解决这些假设。在……里面 目标1，我将使用基因工具以及实时成像和单细胞RNA测序来确定分子 引导迷走神经运动神经元亚群到达心脏和肠道的机制。我会确定候选分子 (转录因子和细胞表面蛋白)决定体神经支配的局部组织 并使用反向遗传学测试这些候选人的作用。在目标2中，我将确定指导机制 迷走神经感觉神经元到适当的器官靶点，并测试感觉神经对 正确建立迷走神经支配。这项工作将揭示一条主要的沟通途径 大脑和器官之间的关系是在发育过程中建立的。

Project Summary / Abstract: During development, the central nervous system establishes precise connections with the body to coordinate organ function. A crucial component of this communication between the brain and body is the vagus nerve (cranial nerve X), which innervates multiple organ systems including the heart, lungs, and digestive tract to regulate blood pressure, heart rate, respiration, and digestion. Despite this important role, the molecular mechanisms guiding the vagus nerve to these organ targets remain completely unknown. We have developed the zebrafish embryo as a powerful model for interrogating vagus nerve development, taking advantage of its optical clarity and genetic accessibility. The vagus is comprised of both ascending sensory fibers that transmit organ state to the brain, and descending motor projections that deliver reciprocal motor commands to the organs. The vagus nerve also targets pharyngeal arch-derived muscles in the head, and the Moens lab has previously described a topographic relationship between the positions of motor neurons in the brain and their targets in the head, and has discovered a spatio-temporal mechanisms for the development of this map. The preliminary data I present here demonstrates that vagal motor projections to the organs are also organized topographically, where vagal motor neurons innervating different organs (heart, stomach, intestines) are spatially segregated within the hindbrain vagus nucleus. I also observe vagal motor projections reaching the viscera much earlier than their sensory counterparts, leading me to hypothesize that correct motor innervation of the viscera is required for subsequent sensory innervation. Here, I propose to address these hypotheses through the following aims. In Aim 1, I will use genetic tools along with live imaging and single-cell RNA sequencing to determine the molecular mechanisms guiding subsets of vagus motor neurons to the heart and gut. I will identify candidate molecules (transcription factors and cell-surface proteins) determining the topographic organization of somatic innervation and test the role of these candidates using reverse genetics. In Aim 2, I will determine the mechanisms guiding vagal sensory neurons to the appropriate organ targets and test the dependence of sensory innervation on the correct establishment of vagal motor innervation. This work will reveal how a major pathway of communication between the brain and organs is established during development.