Development and Patterning of the Enteric Nervous System

项目总结

Project Summary Failure in the onset of gastrointestinal (GI) motility, either in the context of prematurity or GI motility disorders, is a significant cause of neurodevelopmental delay and mortality in the pediatric population. The enteric nervous system (ENS), the local nervous system within the walls of the intestine, is the primary driver of GI motility. We have recently demonstrated that enteric neurons are organized into a macrostructure of circumferentially oriented stripes, which arise from progressive reorganization of enteric neurons from a random array into neuronal stripes. The functional significance of this patterning is not understood, yet GI motility does not arise until a timepoint when neuronal stripes have been established. Further, disruptions to ENS structure, as occur in human diseases like Hirschsprung’s disease and in certain mouse models, are associated with GI dysfunction. Here, we propose to characterize the development of this apparent structure-function relationship in the embryonic and neonatal mouse ENS. We will further investigate the role of the patterning gene Taqpep in ENS patterning and GI function. Taqpep has previously been shown to modulate striped cat coat patterning, and our preliminary data suggest that Taqpep also influences the periodicity of enteric neuronal stripes. To establish a relationship between structure and function during ENS development, we will map GI motility, neuronal diversity, and neural network function onto the progressive striped patterning of the developing ENS (Aim 1). In addition, we will investigate ENS patterning and GI motility in Taqpep mutant mice to determine how subtle alterations to ENS patterning affect GI function (Aim 2). Overall, this project will characterize the relationship between ENS structure and GI motility as well as uncover a molecular mechanism that controls ENS patterning and GI motility. This novel understanding of ENS structure and function will yield critical basic insights into ENS development and provide new avenues to interrogate the pathophysiology and treatment of GI immaturity and pediatric GI motility disorders.