Antral gastrin is the
hormone known to stimulate
acid secretion and proliferation of the gastric corpus epithelium. Patients with mutations in the
multiple endocrine neoplasia type 1 (MEN1) locus, which encodes the
protein menin, develop pituitary
hyperplasia,
insulinomas, and
gastrinomas in the duodenum. We previously hypothesized that loss of menin leads to derepression of the
gastrin gene and hypergastrinemia. Indeed, we show that menin represses JunD induction of
gastrin in vitro. Therefore, we examined whether conditional deletion of Men1 (Villin-Cre and Lgr5-EGFP-IRES-CreERT2), with subsequent loss of menin from the gastrointestinal epithelium, increases
gastrin expression. We found that epithelium-specific deletion of Men1 using
Villin-Cre increased plasma
gastrin,
antral G cell numbers, and
gastrin expression in the antrum, but not the duodenum. Moreover, the mice were hypochlorhydric by 12 mo of age, and gastric
somatostatin mRNA levels were reduced. However, duodenal
mRNA levels of the
cyclin-dependent kinase inhibitor p27(Kip1) were decreased, and cell proliferation determined by Ki67 staining was increased. About 11% of the menin-deficient mice developed
antral tumors that were negative for
gastrin; however,
gastrinomas were not observed, even at 12 mo of age. No
gastrinomas were observed with conditional deletion of Men1 in the Lgr5 stem cells 5 mo after Cre induction. In summary, epithelium-specific deletion of the Men1 locus resulted in hypergastrinemia due to
antral G cell
hyperplasia and a hyperproliferative epithelium, but no
gastrinomas. This result suggests that additional mutations in gene targets other than the Men1 locus are required to produce
gastrin-secreting
tumors.