International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 172 - GASTRIN REGULATION OF SONIC HEDGEHOG PROCESSING CORRELATES WITH MAINTENANCE OF THE GASTRIC MUCOSAL ARCHITECTURE

Zavros Y 1, Eaton K 1, Low MJ 2, Samuelson LC 1, Merchant JL 1

1 University of Michigan, Ann Arbor, United States, 2 Vollum Institute, Oregon Health and Science University, Portland, United States

Gastrin-deficient (G-/-) mice develop severe metaplastic changes in the gastric mucosa in response to hypochlorhydria, bacterial overgrowth and inflammation.  Gastrin is a known trophic hormone for the gastric epithelium.  Sonic hedgehog (Shh), a morphogenic peptide produced by murine parietal and chief cells maintains normal gastric mucosal architecture, but the mechanism is unknown.  The present study investigates the role of gastrin in the regulation of Shh protein expression and processing using the G-/- mouse model.  Compared to 12 month old wild type (WT) and hypergastrinemic somatostatin-deficient (SOM-/-) mice, the hypochlorhydric G-/- mice developed parietal cell atrophy, antral inflammation and metaplasia.  60% of the G-/- mice developed gastric tumors that showed loss of the tumor suppressor gene RUNX3 in isolated tissue.  To confirm that the tumors in the G-/- mice were malignant, cells dissociated from tumors alone grew in soft agar.  Immunofluorescence revealed co-localization of Shh with the parietal cells in the WT animals.  However, Shh expression was decreased in the G-/- mice coincident with loss of parietal cells.  Gastrin-infusion in G-/- mice restored Shh peptide in the parietal cells and increased Shh processing from the 45kDa precursor to the 19kDa active peptide.  Isolated G-/- mouse gastric cells treated with gastrin showed a decrease in the 45kDa precursor in whole cell extract and an increase in the secreted 19kDa Shh peptide.  Therefore, Shh protein expressed in the mouse parietal cells is lost in the absence of gastrin due to reduced expression and peptide processing and this is important for maintenance of normal mucosal architecture.

[an error occurred while processing this directive]