Developmental Genetics of the Enteric Nervous System
The enteric nervous system (ENS) controls motility, mucosal transport, tissue defense and vascular perfusion of the gastrointestinal tract. Abnormalities in development of the ENS give rise to functional gastrointestinal disorders like Hirschsprung disease (HSCR) and neuronal intestinal dysplasia. It has been hypothesized that aberrations in the ENS might contribute as well to the pathogenesis of irritable bowel syndrome and chronic intestinal pseudo-obstruction. My laboratory is pursuing molecular genetic approaches to investigate the development of the enteric nervous system (ENS). We are using mouse models to identify genes that impact ENS progenitors during gastrointestinal ontogeny and to evaluate gene function in the developing ENS by embryological studies.
The Dominant megacolon mouse is the primary disease model being investigated in the laboratory. These mice exhibit reduction of enteric ganglia as well as hypopigmentation, auditory and sensory deficits analogous to those seen in some human HSCR families. Genetic analyses of these animals has identified a mutation (Sox10Dom) in the neural crest transcription factor Sox10 and facilitated identification of similar mutations in the human SOX10 homologue. Sox10Dom mice provide a unique opportunity to identify modifier loci, regions in the genome that modify or influence the degree of severity of the primary mutation on the neural crest progenitors that make up the ENS. On a mixed genetic background Sox10Dom mice exhibit marked variation in the length of the aganglionic segment in the large intestine. This phenotypic variation mimics that seen in human HSCR sibs who carry identical mutations in the SOX10 locus and suggests modifier loci influence development of Sox10 derivatives in both mouse and man. We have established that this variation is due to modifier genes and are pursuing projects to genetically map these in the mouse genome.
To complement our analyses of disease genes that impact the ENS we are also studying the normal developmental processes of ENS formation. To visualize and select for enteric neural crest cells during their migration in the gastrointestinal tract we have generated transgenic mice that drive expression of reporter constructs (LacZ, GFP, CRE) from Sox10 regulatory regions. We are using these transgenic tools to investigate the fate of neural crest cells during development of the enteric nervous system.
Postdoctoral Positions Available
We currently an opening for one Postdoctoral Fellow. One project with support for post-doctoral fellows includes genome wide mapping of modifier loci that alter neural crest development by mapping differentially expressed genes to modifier intervals. The second project with a Postdoctoral opening focuses on lineage analysis in the enteric nervous system and the contribution of neural crest lineages to the developing urogenital tract. Inquiries are welcome.