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

描述(申请人提供)：神经脊是在神经管关闭后不久出现的细胞，并产生各种各样的神经元和非神经元衍生物，构成大量的头部结构和周围神经系统。这些细胞从一种不活动的紧密贴壁的细胞类型转变为一种高度运动的细胞类型，使它们能够在整个胚胎中迅速迁移，并到达它们分化的遥远区域。此外，神经脊细胞包括干细胞样群，可产生神经元、神经胶质细胞、黑素细胞、面骨、角膜等。神经脊细胞误导或死亡造成的出生缺陷范围从腭裂(神经脊未能关闭两侧面部)到先天性巨结肠/巨结肠(神经脊未能定植于结肠)到神经纤维瘤病(源于神经脊的散发性小肿瘤)。关于引导神经脊迁移过程的潜在机制，人们知之甚少。我的初步数据显示，狭缝轴突化学反应物在进入一组神经脊的肠道而不是另一组神经脊的时间上很重要。这项拟议的研究的目的是检查Sit分子的机制，可能是通过其假定的Robo受体废除躯干，而不是迷走神经脊移。具体地说，该项目将：a)研究Robo受体在排斥细胞内躯干神经脊迁移中的功能，b)确定Sit在阻止躯干而不是迷走神经峰进入肠道中的作用。综上所述，这些实验将有助于我们理解Sit化学触发剂通过防止躯干神经脊迁移到其区域以及在躯干脊细胞中观察到的排斥效应是否由Robo介导而在肠道形成中发挥的多种作用。叙述这项拟议研究的目标是研究Sit和Robo分子在迷走神经和躯干神经脊的引导和迁移中的作用和相互作用。总而言之，初步数据表明，除了化学驱避剂分子之外，还有更多的分子可以切割，它们可能参与了除指导之外的其他功能。然而，目前尚不清楚为什么躯干神经脊细胞不会进入形成的肠道，而迷走神经则会进入。这项建议的目的是通过观察缝隙在迷走神经和主干脊细胞迁移中的作用以及寻找Robo在这一现象中的作用来进一步研究这种可能性。这些实验的意义来自于它研究神经脊迁移和狭缝分子在发育过程中引导它们的机制的新方法。非常重要的是，我们仍然不清楚SIts抑制和刺激躯干运动的双重作用机制，而不是迷走神经脊细胞。我建议通过多方面的方法来研究这些问题：胚胎学和细胞生物学/分子。

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.