Placode lineage contribution to Hirschsprung's disease

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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).