Sonic hedgehog regulates gastric gland morphogenesis in man and mouse

Background & Aims: Gastric epithelial renewal is an asymmetric process. A s tem cell located halfway up the tubular unit gives rise to both a basal gla nd region and a luminal pit compartment, but the mechanisms responsible for the maintenance of this asymmetry are obscure. We investigated whether Son ic hedgehog (Shh), an established polarizing signal protein during developm ent, is expressed and functional in the adult human and murine stomach. Met hods. Expression of Shh and putative transcriptional targets was investigat ed using immunoblot and immunohistochemistry. Mice were treated with the Sh h inhibitor cyclopamine and examined for expression levels of Shh targets a nd proliferation of gastric epithelial cells. Results: Shh was expressed in the stomach. In cyclopamine-treated mice, we observed decreased expression of HNF3 beta, Islet (IsI)-1 and BMP4, 3 putative Shh target genes. Inhibit ion of Shh markedly enhanced gastric epithelial proliferation and affected the cell cycle of gastric epithelial gland cells, whereas pit cells remaine d unaffected. Conclusions: Shh controls the expression of at least 3 factor s important for epithelial differentiation and is a negative regulator of g astric gland cell proliferation. Shh is a candidate polarizing signal in th e maintenance of gastric pit-gland asymmetry.