As a master component of endosomal sorting complex required for transport proteins,hepato-cyte growth factor-regulated tyrosine kinase substrate (Hgs) participates multiple cellular be-haviors.However,the physiological role of Hgs in smooth muscle cells (SMCs) is by far unknown.Here we explored the in vivo function of Hgs in SMCs by using a conditional gene knockout strategy.Hgs deficiency in SMCs uniquely led to a progressive dilatation of esophagus with a remarkable thinning muscle layer.Of note,the mutant esophagus showed a decreased contractile responsiveness to potassium chloride and acetylcholine stimulation.Furthermore,an increase in the inhibitory neurites along with an intense infiltration of T lymphocytes in the mucosa and muscle layer were observed.Consistently,Hgs deficiency in SMCs resulted in a disturbed expression of a set of genes involved in neurotrophin and inflammation,suggesting that defective SMC might be a novel source for excessive production of cytokines and chemokines which may trigger the neu-ronal dysplasia and ultimately contribute to the compromised esophageal motility.The data suggest potential implications in the pathogenesis of related diseases such as gastroesophageal reflux disease.