Functional analysis of early vagal neural crest and ENS development

早期迷走神经嵴和 ENS 发育的功能分析

• 批准号: 9113056
• 负责人: Rosa A Uribe
• 金额: $ 5.8万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2017-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113056
• 关键词: Attention; Birth; Blood flow; Chickens; Chronic; Complex; Congenital Megacolon; Constipation; Cues; Defect; Destinations; Development; Distal; Dorsal; Ectopic Expression; Embryo; Enteral; Enteric Nervous System; Environment; Food; Foundations; Ganglia; Genetic; Goals; Health; Human; Immigration; Intestinal Motility; Intestinal Obstruction; Intestines; Knowledge; Lead; Length; Mediator of activation protein; Megacolon; Mesenchyme; Methods; Molecular; Movement; Mus; Neural Crest; Neural Crest Cell; Neural tube; Neuroglia; Neurons; Pathway interactions; Peripheral Nervous System; Phase; Play; Population; Primitive foregut structure; Process; Regulation; Research; Research Proposals; Resolution; Role; Series; Signal Pathway; Solid; Stem cells; Testing; Tissues; Translational Research; Tretinoin; Zebrafish; base; cell fate specification; cell motility; cell type; hindbrain; improved; in vivo; loss of function; migration; nervous system development; research study; response; zebrafish development

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.

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细胞组成，控制肠道蠕动并调节肠壁内的血流。在发育过程中，ENS 由迷走神经嵴细胞产生，这些细胞从尾后脑水平的神经管移出。到达前肠后，迷走神经衍生的肠神经嵴细胞沿着发育中的肠道尾部迁移并分化为 肠神经元和神经胶质细胞类型。向肠道或沿肠道迁移的异常或沿肠道迁移的异常会导致出生异常，例如先天性巨结肠症，其中肠道的远端部分缺乏肠神经元或神经胶质细胞，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 ENS 发育后期的肠道中，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。本提案中的实验将利用斑马鱼和鸡胚胎，以增强我们对调节迷走神经嵴和 ENS 发育早期阶段的机制的理解。鸡和斑马鱼的胚胎都是在体外发育的，因此可以轻松进行实验操作和观察。此外，斑马鱼胚胎在发育过程中是透明的，可以对神经嵴细胞迁移进行高分辨率分析。具体目标是 1. 研究 Meis3 在斑马鱼肠神经嵴发育中的作用，以及 2. 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着提高我们对肠神经嵴细胞迁移和命运规范的基本理解，从而提供 为上游转化研究工作奠定了坚实的基础。