Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice

doi:10.1016/S0006-291X(02)00480-1

Biochemical and Biophysical Research Communications

Volume 294, Issue 2, 7 June 2002, Pages 470-479

https://doi.org/10.1016/S0006-291X(02)00480-1 Get rights and content

Abstract

Gastric intestinal metaplasia occurs as a pathological condition in the gastric mucosa. To clarify how an intestine-specific homeobox gene, Cdx2, affects the morphogenesis of gastric mucosa, we generated transgenic mice expressing Cdx2 in parietal cells. Until Day 18 after birth, the number of parietal cells inthegastric mucosa of transgenic mice was the same as for their normal littermates. However, at Day 19, we detected several glands in which parietal cells disappeared and the proliferating zone moved from the isthmus to the base of the glands. Thereafter, parietal cells decreased gradually and disappeared at Day 37. All of the gastric mucosal cells, except for enterochromaffin-like (ECL) cells, were completely replaced by intestinal metaplasia, consisting of goblet cells, enteroendocrine cells, and absorptive cells expressing alkaline phosphatase. Pseudopyloric gland metaplasia was also formed. The transgenic mouse is a very useful model for clarifying physiological differentiation of gastric and intestinal cell lineages and analyzing the molecular events from intestinal metaplasia to adenocarcinoma.

Section snippets

Methods

Generation of transgenic mice. Cdx2 cDNA was inserted into the EcoRI site of pBS/HKATPase, yielding pBS/HKATP/Cdx2. pBS/HKATPase contains nucleotides −1417 to +15 of the rat H⁺/K⁺-ATPase β-subunit gene in pBluescript II SK(+). TheH⁺/K⁺-ATPase/Cdx2 insert in pBS/HKATP/Cdx2 was released, purified, and then used for pronuclear injection of 500 C57BL/6 oocytes. Injected eggs were transferred to pseudopregnant Swiss Webster females using standard techniques [19]. Eighty live-born mice were screened

A chronological analysis of the change from gastric mucosa to intestinal metaplasia

To investigate whetherthe intestine-specific transcription factor Cdx2 can promote the development of intestinal metaplasia in the stomach, we generated transgenic mice with stomach-specific expression of Cdx2. The promoter of the noncatalytic β-subunit gene of rat H⁺/K⁺-ATPase was used to direct expression of Cdx2 in the parietal cell lineage. Cdx2 transgenic mice werefertile and were indistinguishable from their wild-type littermates in behavior, outward appearance, and weight. Until Day 18

Discussion

We have established transgenic mice expressing Cdx2 in the gastric mucosa as a model for analyzing the relationship between Cdx2 protein expression and intestinal metaplastic change. Remarkably, expression of a single gene, Cdx2, completely changed gastric mucosa to intestinal metaplasia, indicating that Cdx2 has an essential role as a transcription factor for intestinal differentiation.

The mouse intestinal epithelium contains four principal terminally differentiated cell types: absorptive

Acknowledgments

We are grateful to Dr. T. Takeuchi (Gunma University) for providing the pBS/HKATPase plasmid, Dr. K. Miyamoto (Tokushima University) for antibodies for sucrase and PepT1, and P. Traber (University of Pennsylvania) for the mouse Cdx2 expression vector pRc/CMV-Cdx-2. The expert technical assistance of Ms. M. Nozawa, S. Terauchi, and K. Sasaki is much appreciated.

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Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice

Abstract

Section snippets

Methods

A chronological analysis of the change from gastric mucosa to intestinal metaplasia

Discussion

Acknowledgments

Gastroenterology

Gastroenterology

J. Biol. Chem.

Gastroenterology

Genomics

Phenotypic and genotypic events in gastric carcinogenesis

Cancer Res.

Tumor production in the glandular stomach and alimentary tract of the rat by N-methyl-N′-nitro-N-nitrosoguanidine

Cancer Res.

Periodical observations of the glandular stomach in rat treated with N-methyl-N′-nitro-N-nitrosoguanidine

Nagoya Med. J.

Histogenesis and autoradiography of adenocarcinoma of the glandular stomach in rats induced by oral administration of N,N′-2,7-fluorenylenebisacetamide combined with irradiation to the stomach region

Gann

Experimental intestinal metaplasia of gastric mucosa of rats and its relationship to carcinoma

Neoplasma

Achlorhydria, gastric mucosal atrophy and gastric neoplastic lesions in rats, mice and hamsters treated with an anticholinergic drug, propantherine bromide, and a carcinogen 20-methylcholanthrene

Can. J. Surg.

Morphological and biochemical changes in the gastric mucosa of A/HeJ mice injected with a xenogeneic stomach antigen

Acta Pathol. Jpn.

Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia

J. Gastroenterol.

Tumor production in the glandular stomach and alimentary tract of the rat by N-methyl-N^′-nitro-N-nitrosoguanidine

Periodical observations of the glandular stomach in rat treated with N-methyl-N^′-nitro-N-nitrosoguanidine

Histogenesis and autoradiography of adenocarcinoma of the glandular stomach in rats induced by oral administration of N,N^′-2,7-fluorenylenebisacetamide combined with irradiation to the stomach region