Placode lineage contribution to Hirschsprung's disease

描述(申请人提供)：先天性巨结肠症是一种先天性肠道动力障碍，由神经脊向胃肠道迁移失败引起。神经Cres负责肠道神经系统的形成，它们的缺失会导致末端肠道无神经节段，从而导致无法促进蠕动收缩。这项建议中描述的新观察结果导致了一个模型，在该模型中，胎盘细胞也迁移和定植于肠道，并选择性地产生内源性感觉神经元 肠神经节，而神经脊细胞贡献非感觉群体(运动神经元、中间神经元和神经胶质)。在这一应用中，我提议进行实验，以确定肠道神经系统中的肠道胎盘的命运，并解决内皮素和Ret信号如何控制神经脊和胎盘细胞在肠道的迁移和定植。此外，我提出了一种模型，在该模型中，肺丛的固有气道神经节也来自胎盘和神经脊，这将为先天性中枢性低通气综合征(CCHS)的发病机制提供新的见解。

DESCRIPTION (provided by applicant): Hirschsprung's disease is a congenital gut motility disorder caused by the failure of neural crest migration to the gastrointestinal tract. Neural cres is responsible for formation of the enteric nervous system, and their absence results in an aganglionic segment in the terminal bowel, which results in a failure to promote peristaltic contraction. New observations described in this proposal lead to a model in which placode cells also migrate and colonize the gut and selectively give rise to the intrinsic sensory neurons of the enteric ganglia, whereas neural crest cells contribute to non-sensory population (motor neurons, interneurons, and glia). In this application, I propose experiments to define the fate of enteric placode in the enteric nervous system, and to address how endothelin and Ret signaling control both neural crest and placode cell migration and colonization of the gut. Furthermore, I propose to address a model in which the intrinsic airway ganglia of the pulmonary plexus are also derived from both placode and neural crest, which will provide new insight into pathogenesis of the Hirschsprung's disease associated syndrome, Congenital central hypoventilation syndrome (CCHS).