Esophageal atresia (EA) is the most common congenital disorder of the esophagus with a worldwide incidence of about 1 in 3,500 live births. EA can occur as an isolated ?nding, or in combination with either syndromic or non-syndromic developmental anomalies. Left untreated, EA is a fatal disorder because the atretic segment obstructs the esophagus. Fortunately, it can be cured surgically in nearly all infants, however the majority suffer from severe gastroesophageal re?ux and dysphagia as a result of impaired esophageal motility. Although the cause of EA is not known, a genetic component is predicted based on its occurrence in complex developmen- tal syndromes and its higher incidence in monozygotic vs. dizygotic twins. No single gene mutations have been conclusively shown to cause EA. We have developed the ?rst animal model of isolated EA by engineering a mutation in the smooth muscle myosin heavy chain gene (Myh11) that we have previously shown alters myosin regulation. In zebra?sh, the identical mutation causes invasive expansion of the intestine. In mice the predomi- nant phenotype is EA, although invasive-like intestinal lesions are detected. The mutation disrupts smooth muscle contractility as a result of altered myosin regulation. This suggests that genetic variants in MYH11 and other smooth muscle regulatory genes could cause both EA and its associated esophageal motility disorders. Preliminary transcriptional pro?ling studies of esophagi from Myh11 mutants before the EA phenotype is de- tected showed altered regulation of genes involved in nervous system and striated muscle development. This suggest that defects in esophageal neuromuscular function may be an intrinsic defect associated with EA that arises independently of atresia. Supporting this, immunostainings show altered esophageal nerve ?ber density, reduced number and size of esophageal ganglia and altered striated muscle development in mutant esophagi The goal of this proposal is to expand these ?ndings by examining these and other gene expression changes in older Myh11 mutants, by quantifying changes in neuronal density and neuronal subtypes, and by conducting in vitro functional analyses in primary cultures of esophageal neurons.
We have developed a novel mouse model of the human congenital disorder esophageal atresia (EA) by introducing a mutation in the smooth muscle myosin heavy chain gene Myh11 that disrupts its regulation. We hypothesize that characterizing gene expression changes in the mutant esophagi and in esophagi of infants with EA will help us understand the cause of EA and its associated motility symptoms.
