Gastrin is a peptide hormone important in the regulation of both acid secretion and differentiation of oxyntic mucosal cells of the stomach. To further elucidate the role of gastrin in the growth and development of the gastrointestinal tract, we have generated mice that are deficient in gastrin.Gastrin-deficient mice were generated through targeted gene disruption. Gastric and colonic architecture were determined by routine histology and immunohistochemical techniques. Proliferation was assessed by 5-bromo-2'-deoxyuridine incorporation.Targeted disruption of the gastrin gene resulted in mice incapable of expressing gastrin messenger RNA (mRNA) or producing gastrin peptide. This deficiency led to a marked change in gastric architecture, with a decrease in number of parietal and enterochromaffin-like cells and an increase in number of mucous neck cells. There was no difference in the proliferation labeling index of the stomach in gastrin-deficient mice (3.04% +/- 0.33%) compared with wild-type littermates (3.15% +/- 0.18%). The colon of gastrin-deficient mice seemed normal histologically, although there was a decreased proliferation labeling index (2.97% +/- 0.52%) compared with wild-type littermates (4.71% +/- 0.44%; P < 0.01).Gastrin is important in regulating the differentiation of the gastric mucosa and is a trophic factor for the colonic mucosa.