Reprogramming of intestinal differentiation and intercalary regeneration inCdx2mutant mice

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Abstract
The homeobox geneCdx2, a homologue of theDrosophilagenecaudal, has been implicated in the control of cell differentiation in the intestinal epithelium. Recently, we showed that mice in which one allele of theCdx2gene had been inactivated by homologous recombination developed multiple intestinal polyp-like lesions that did not expressCdx2and that contained areas of squamous metaplasia in the form of keratinizing stratified squamous epithelium, similar to that occurring in the mouse esophagus and forestomach. We have now examined colonic lesions from 98Cdx2+/− mice and report that the lesions are composed of heterotopic stomach and small intestinal mucosa. We conclude thatCdx2directs endodermal differentiation toward a caudal phenotype and that haploinsufficient levels of expression in the developing distal intestine lead to homeotic transformation to a more rostral endodermal phenotype, such as forestomach epithelium that does not expressCdx2during normal development. Intercalary growth (epimorphic regeneration), which previously has never been described in mammals, then occurs, resulting in the ordered “filling in” of tissue types at the discontinuity between the gastric and colonic epithelia. This intercalary growth in a restricted space results in the formation of the polypoid lesions observed.