No abstract

Transgenic mice (hGAS) that overexpress human progastrin are more susceptible than wild-type mice (FVB/N) to the induction of colonic aberrant crypt foci (ACF) and adenomas by the chemical carcinogen azoxymethane. We have previously shown significantly increased levels of colonic mitosis in hGAS compared with FVB/N mice after gamma-radiation. To investigate whether the effects of progastrin observed in hGAS colon require the presence of other forms of circulating gastrin, we have crossed hGAS (hg(+/+)) with gastrin knockout (G(-/-)) mice to generate mice that express progastrin and no murine gastrin (G(-/-)hg(+/+)). After azoxymethane, G(-/-)hg(+/+) mice developed significantly more ACF than control G(-/-)hg(-/-) mice (which do not express any forms of gastrin). G(-/-)hg(+/+) mice also exhibited significantly increased colonic mitosis both before and after exposure to 8 Gray Gy gamma-radiation or 50 mg/kg azoxymethane compared with G(-/-)hg(-/-). Treatment of G(-/-)hg(-/-) mice with synthetic progastrin (residues 21-101 of human preprogastrin) or G17 extended at its COOH terminus corresponding to the COOH-terminal 26-amino-acid residues of human preprogastrin (residues 76-101, G17-CFP) resulted in continued colonic epithelial mitosis after gamma-radiation, whereas glycine-extended gastrin-17 and the COOH-terminal tryptic fragment of progastrin [human preprogastrin-(96-101)] had no effect. Immunoneutralization with an antibody against G17-CFP before gamma-radiation significantly decreased colonic mitosis in G(-/-)hg(+/+) mice to levels similar to G(-/-)hg(-/-). We conclude that progastrin does not require the presence of other forms of gastrin to exert proliferative effects on colonic epithelia and that the portion of the peptide responsible for these effects is contained within amino acid residues 76-101 of human preprogastrin.

Kirton, C. M., T. Wang, and G. J. Dockray. Regulation of parietal cell migration by gastrin in the mouse. Am J Physiol Gastrointest Liver Physiol 283: G787-G793, 2002. First published April 24, 2002 10.1152/ajpgi.00538.2001.-Recent studies suggest that gastrin regulates parietal cell maturation. We asked whether it also regulates parietal cell life span and migration along the gland. Dividing cells were labeled with 5Ј-bromo-2Ј-deoxyuridine (BrdU), and parietal cells were identified by staining with Dolichos biflorus lectin. Cells positive for D. biflorus lectin and BrdU were reliably identified 10-30 days after BrdU injection in mice in which the gastrin gene had been deleted by homologous recombination (Gas-KO) and wild-type (C57BL/6) mice. The time course of labeling was similar in the two groups. The distribution of BrdU-labeled parietal cells in wild-type mice was consistent with migration to the base of the gland, but in Gas-KO mice, a higher proportion of BrdU-labeled cells was found more superficially 20 and 30 days after BrdU injection. Conversely, in transgenic mice overexpressing gastrin, BrdU-labeled parietal cells accounted for a higher proportion of the labeled pool in the base of the gland 10 days after BrdU injection. Gastrin, therefore, stimulates movement of parietal cells along the gland axis but does not influence their life span. gastric epithelium; cell migration; bromodeoxyuridine THE ORGANIZATION OF THE EPITHELIUM throughout the gut is maintained by cellular proliferation followed by migration and differentiation. Proliferating cells in the gastric epithelium are located in the isthmus region of the glands (7). Cells that leave the cell cycle may migrate toward the surface, adopting a mucus-secreting phenotype, or toward the base of the gland, where the main differentiated cell types are parietal, chief, and endocrine cells. In addition, the latter cell types migrate to arrange themselves in characteristic tubular ensembles that constitute the gastric glands. This process is thought to depend on cell-cell and cell-matrix interactions, but little is known of the relevant regulatory mechanisms.It is well recognized that gastrin influences the organization of the gastric epithelium and acutely regulates acid secretion (17). Elevated plasma gastrin concentrations are associated with increased parietal cell mass (15) and hyperplasia of histamine-producing enterochromaffin-like cells (1,12,14). Mice in which the gastrin gene has been deleted by homologous recombination (Gas-KO) are achlorhydric and do not respond to acute administration of the acid secretagogues gastrin, histamine, and carbachol (6). They do, however, secrete acid after treatment with gastrin for Ն24 h (2, 6). These observations, therefore, suggest that gastrin plays a role in parietal cell maturation. Interestingly, in transgenic mice with moderate hypergastrinemia (Ins-Gas mice), there is an initial increase in parietal cell numbers, although this is followed (Ͼ4 mo) by a progressive loss of glandular cells and foveolar hype...

No abstract

No abstract