Functional analysis of early vagal neural crest and ENS development

描述（由申请人提供）：肠神经系统（ENS）是周围神经系统中最复杂和最大的部分。ENS由一系列复杂的相互连接的神经元和神经胶质组成，它们控制肠运动并调节肠壁内的血流。在发育过程中，ENS起源于迷走神经嵴细胞，这些细胞从尾侧后脑水平的神经管迁移。在到达前肠后，迷走神经源性肠神经嵴细胞沿发育中的肠向尾侧沿着迁移，并分化为 肠神经元和神经胶质细胞类型。向肠道或沿着肠道或沿着肠道迁移的障碍导致出生异常，如先天性巨结肠症，其中肠道的远端部分缺乏肠神经元或神经胶质，导致巨结肠和慢性便秘。虽然许多研究注意力集中在肠神经嵴细胞迁移的功能分析上， 肠神经嵴细胞在ENS发育后期的作用，调节其迁移的分子机制以及早期迷走神经和肠神经嵴细胞身份的指定知之甚少。在这项建议中的实验将利用斑马鱼和鸡胚胎，以提高我们的理解，调节迷走神经嵴和ENS发育的早期阶段的机制。鸡和斑马鱼的胚胎都是外部发育的，这使得实验操作和观察变得容易。此外，斑马鱼胚胎在发育过程中是透明的，允许对神经嵴细胞迁移进行高分辨率分析。具体目标是1.探讨Meis 3在斑马鱼肠神经嵴发育中的作用。阐明Hoxb5在迷走神经和肠神经嵴发育中的作用和调节。这些实验的结果将显著提高我们对肠神经嵴细胞迁移和命运特化的基本理解，从而提供了一个新的研究方向。 坚实的基础上，基础上游翻译研究的努力。

DESCRIPTION (provided by applicant): The enteric nervous system (ENS) is the most complex and largest portion of the peripheral nervous system. The ENS is comprised of a complex series of interconnected neurons and glia that control intestinal motility and regulate blood flow within the gut wall. During development, ENS arises from vagal neural crest cells that emigrate from the neural tube at caudal hindbrain levels. Upon reaching the foregut, the vagal-derived enteric neural crest cells migrate caudally along the developing gut and differentiate into enteric neurons and glial cell types. Abnormalities in migration to or along the gut or along resul in birth anomalies like Hirschsprung's Disease, in which the distal portion of the intestine is devoid of enteric neurons or glia, resulting in megacolon and chronic constipation. While much research attention has focused on the functional analysis of enteric neural crest cell migration in the gut during later phases of ENS development, the molecular mechanisms that regulate their migration and the designation of early vagal and enteric neural crest cell identity is poorly understood. The experiments in this proposal will utilize zebrafish and chicken embryos in order to enhance our understanding of the mechanisms that regulate early phases of vagal neural crest and ENS development. Both chicken and zebrafish embryos develop externally, allowing for easy experimental manipulation and observation. Furthermore, zebrafish embryos are transparent during development allowing for high-resolution analysis of neural crest cell migration. The specific aims are to 1. Investigate the role of Meis3 in development of the zebrafish enteric neural crest, and 2. Elucidate the role and regulation of Hoxb5 in vagal and enteric neural crest development. The results of these experiments will significantly improve our basic understanding of enteric neural crest cell migration and fate specification, thus providing a solid foundation on which to base upstream translational research endeavors.