Loss of Parietal Cell Expression of Sonic Hedgehog Induces Hypergastrinemia and Hyperproliferation of Surface Mucous Cells

Background & Aims

Sonic Hedgehog (Shh) is expressed in the adult stomach, but its role as a gastric morphogen is unclear. We sought to identify mechanisms by which Shh might regulate gastric epithelial cell function and differentiation.

Methods

Mice with a parietal cell–specific deletion of Shh (HKCre/Shh^KO) were created. Gastric morphology and function were studied in control and HKCre/Shh^KO mice between 1 and 8 months of age.

Results

In contrast to control mice, HKCre/Shh^KO mice developed gastric hypochlorhydria, hypergastrinemia, and a phenotype that resembled foveolar hyperplasia. The fundic mucosa of HKCre/Shh^KO mice had an expanded surface pit cell lineage that was documented by increased incorporation of bromodeoxyuridine and was attributed to the hypergastrinemia. Compared with controls, numbers of total mucous neck and zymogen cells were significantly decreased in stomachs of HKCre/Shh^KO mice. In addition, zymogen and neck cell markers were coexpressed in the same cell populations, indicating disrupted differentiation of the zymogen cell lineage from the mucous neck cells in the stomachs of HKCre/Shh^KO mice. Laser capture microdissection of the surface epithelium, followed by quantitative reverse-transcription polymerase chain reaction, revealed a significant increase in expression of Indian Hedgehog, glioma-associated oncogene homolog 1, Wnt, and cyclin D1. Laser capture microdissection analysis also showed a significant increase in Snail with a concomitant decrease in E-cadherin.

Conclusions

In the stomachs of adult mice, loss of Shh from parietal cells results in hypochlorhydria and hypergastrinemia. Hypergastrinemia might subsequently induce increased Hedgehog and Wnt signaling in the surface pit epithelium, resulting in hyperproliferation.

Abbreviations used in this paper: BrdU, bromodeoxyuridine, Gli1, glioma-associated oncogene homolog 1, GSII, Griffonia simplicifolia II, IF, intrinsic factor, Ihh, Indian Hedgehog, LCM, laser capture microdissection, PgC, pepsinogen, Ptch, Patched, qRT-PCR, quantitative reverse-transcription polymerase chain reaction, Shh, Sonic Hedgehog, Smo, Smoothened, TGF, transforming growth factor, UEAI, Ulex europaeus I