Grant: Discovery Grants Program - Individual

The enteric nervous system is the largest and most complex part of the peripheral nervous system. It is found throughout the length of the intestines and is responsible for normal bowel motility. Thus, abnormal development of the ENS is the main cause of gut motility disorders such as aganglionic megacolon. This lethal condition is caused by the absence of an intact ENS in the terminal regions of the gut; the affected segment stays contracted leading to intestinal obstruction, dilation and severe constipation. Human clinical cases and animal models have led to the identification of several genes important for ENS development. Nevertheless, given the complexity of the ENS, our understanding of its formation is far from complete. In order to identify new genes/loci important for ENS development, I have performed an insertional mutation screens in transgenic mice. Due to random insertion of transgenes in the mouse genome, this screen allowed the identification of three lines of mice, named ""Dapple"", ""Dominant Spot"" and ""Holstein"" that display an aganglionic megacolon phenotype. Genetic studies to date have shown that at least the mutations for Dapple and Dominant Spot are in new genes/loci. The proposed research program is aimed at identifying and characterizing the genes affected by these mutations with a special focus on the Dapple line. Molecular studies to date suggest that reduced expression of the new gene Kiaa1279 is responsible of the Dapple megacolon phenotype. In this regard, I now propose studies to understand the function of the Kiaa1279 gene product in ENS development. Overall, this research program will significantly expand the current limited knowledge of ENS development at the genetic, molecular and cellular levels. This new knowledge will represent key contributions to an important research field which is currently understudied in Canada.