Role of Robo receptor in the formation of the enteric nervous system

Robo受体在肠神经系统形成中的作用

• 批准号: 7304410
• 负责人: Maria Elena de Bellard
• 金额: $ 20.55万
• 依托单位: CALIFORNIA STATE UNIVERSITY NORTHRIDGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7304410
• 关键词: Address; Area; Biological; Cells; Cessation of life; Cleft Palate; Colon; Congenital Abnormality; Cornea; Data; Development; Disease; Distant; Embryo; Enteric Nervous System; Face; Failure; Genus Cola; Goals; Head; Immigration; Mediating; Megacolon; Mesenchyme; Molecular; Neural Crest; Neural Crest Cell; Neural Tube Closure; Neurofibromatoses; Neuroglia; Neurons; Numbers; Peripheral Nervous System; Play; Population; Process; Range; Role; Side; Stem cells; Structure; Time; Tube; cell motility; cell type; face bone structure; melanocyte; migration; novel strategies; prevent; receptor; research study; stem; tumor

DESCRIPTION (provided by applicant): The neural crest are cells that emerge shortly after neural tube closure and give rise to the wide variety of neuronal and non-neuronal derivatives that make a large number of head structures and the peripheral nervous system. These cells go from a non-motile, closely adherent cell type, to a highly motile one that allows them to migrate rapidly throughout the embryo and reach distant areas where they differentiate. In addition, neural crest cells encompass a stem cell- like population that can give rise to neurons, glia, melanocytes, facial bone, cornea, etc. The range of birth defects caused by neural crest cells misdirection or death goes from cleft palate (failure of the neural crest to close both sides of the face) to Hirschprung disease/Megacolon (failure of the neural crest to colonize the colon) to Neurofibromatosis (scattered small tumors of neural crest origin). Little is known about the underlying mechanism directing the process of neural crest migration. My preliminary data showed that Slit axonal chemorepellants are important in timing the entry into the gut of one population of neural crest versus another. The goal of the proposed study is to examine the mechanism by which Slit molecules, possibly through its putative Robo receptor repeal trunk, not vagal neural crest migration. Specifically, this project will: a) Examine the function of Robo receptors in repulsion of trunk neural crest migration in cells, b) Determine the role of Slit in preventing trunk, but not vagal neural crest from entering the gut. In summary, these experiments will contribute to our understanding of the multiple roles that Slit chemorepellants play in the formation of the gut by preventing trunk neural crest migration into its region and if the repulsive effects observed in trunk crest cells are Robo mediated. Narrative The goal of the proposed study is to examine the roles and interactions between Slit and Robo molecules have on vagal and trunk neural crest guidance and migration. Altogether preliminary data suggest that there is more to Slit molecules than being just a chemorepellant molecules, that they may be involved in other functions besides guidance. However, it is still not known why trunk neural crest cells will not enter the forming gut while vagal will. It is the aim of this proposal to investigate further this possibility by looking at Slit function in vagal and trunk crest migration of neural crest cells and in looking for Robo's role in this phenomenon. The significance of these experiments stems from its novel approach to study neural crest migration and the mechanism by which Slit molecules guide them during development. Very important, we still do not understand the mechanisms by which Slits have a dual function in both inhibiting and stimulating motility of trunk, not vagal neural crest cells. I propose to study these questions through a multi-faceted approach: embryological and cell biological/molecular.

描述（由申请人提供）：神经嵴是神经管闭合后不久出现的细胞，产生各种神经元和非神经元衍生物，形成大量头部结构和周围神经系统。这些细胞从一种非活动的、紧密贴壁的细胞类型转变为一种高度活动的细胞类型，使它们能够在整个胚胎中快速迁移并到达它们分化的远处区域。此外，神经嵴细胞包含类干细胞群，可以产生神经元、胶质细胞、黑素细胞、面骨、角膜等。神经嵴细胞误导或死亡引起的出生缺陷范围从腭裂（神经嵴无法闭合面部两侧）到先天性巨结肠（神经嵴无法定植结肠）到 神经纤维瘤病（神经嵴起源的分散性小肿瘤）。对于指导神经嵴迁移过程的潜在机制知之甚少。我的初步数据表明，狭缝轴突化学排斥剂对于确定一组神经嵴与另一组神经嵴进入肠道的时间很重要。这项研究的目的是检查 Slit 分子可能通过其假定的 Robo 受体废除主干，而不是迷走神经嵴迁移的机制。具体来说，该项目将：a) 检查 Robo 受体在细胞中排斥躯干神经嵴迁移的功能，b) 确定 Slit 在阻止躯干神经嵴进入肠道中的作用，但不能阻止迷走神经嵴进入肠道。总之，这些实验将有助于我们了解 Slit 化学排斥剂通过阻止躯干神经嵴迁移到肠道区域中所发挥的多重作用，以及在躯干嵴细胞中观察到的排斥效应是否是 Robo 介导的。叙述 本研究的目标是检查 Slit 和 Robo 分子之间对迷走神经和躯干神经嵴引导和迁移的作用和相互作用。初步数据表明，Slit 分子不仅仅是化学排斥分子，它们可能还涉及除引导之外的其他功能。然而，目前尚不清楚为什么躯干神经嵴细胞不会进入正在形成的肠道，而迷走神经却会。本提案的目的是通过观察神经嵴细胞迷走神经和躯干嵴迁移中的狭缝功能并寻找 Robo 在这一现象中的作用来进一步研究这种可能性。这些实验的意义源于其研究神经嵴迁移的新方法以及 Slit 分子在发育过程中引导神经嵴迁移的机制。非常重要的是，我们仍然不了解狭缝具有抑制和刺激躯干运动而不是迷走神经嵴细胞运动的双重功能的机制。我建议通过多方面的方法研究这些问题：胚胎学和细胞生物学/分子。