Reprogramming of intestinal differentiation and intercalary regeneration inCdx2mutant mice

Abstract

The homeobox gene Cdx2, a homologue of the Drosophila gene caudal, has been implicated in the control of cell differentiation in the intestinal epithelium. Recently, we showed that mice in which one allele of the Cdx2 gene had been inactivated by homologous recombination developed multiple intestinal polyp-like lesions that did not express Cdx2 and 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 98 Cdx2؉͞؊ mice and report that the lesions are composed of heterotopic stomach and small intestinal mucosa. We conclude that Cdx2 directs 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 express Cdx2 during 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.

Cdx1, a dispensable homeobox gene for gut development with limited effect in intestinal cancer

“…Yet a subtle modification occurred in the distal colon of Cdx1 À/À mice where Muc2 expression extended deeper downwards the glands compared to wild-type animals (Supplementary Figure 2D). The absence of morphological phenotype in the gut of Cdx1 À/À mice contrasts with the phenotype of gastric-type heteroplasia reported in Cdx2 þ /À animals (Beck et al, 1999). Since Cdx1, like Cdx2, exhibits the intrinsic capacity of driving the intestinal fate when ectopically expressed (Mutoh et al, 2004), these data suggest that Cdx2 compensates for Cdx1 deficiency in the gut, as it precedes and is necessary for Cdx1 onset during intestinal development Bonhomme et al, 2003).…”

“…By mid-gestation onward, they are turned off except for Cdx1 and Cdx2 in the gut epithelium and Cdx4 in haematopoietic stem cells (Bansal et al, 2006). In the gut, Cdx2 is crucial for intestinal fate specification and differentiation (Beck et al, 1999), and it also has a tumour suppressor function in the adult colon (Bonhomme et al, 2003;Gross et al, 2008). Cdx1 is the second gutspecific Cdx-type gene.…”

The dichotomy in carcinogenesis of the distal esophagus and esophagogastric junction: intestinal-type vs cardiac-type mucosa-associated adenocarcinoma

“…The association of an intestinal or mixed immunophenotype (especially CDX2 expression) with intestinal-type mucosa-associated adenocarcinoma is in keeping with current understanding of the pathogenesis of intestinal metaplasia. Normally CDX2 is localized to the small and large bowel, 44,45 where it is responsible for the maintenance of intestinal phenotype, 21,22 including the upregulation of MUC2, an intestinal-type mucin, in goblet cells. 31,46 CDX2 expression has also been reported in 54% of gastric carcinomas, often in conjunction with MUC2 expression.…”

“…Immunohistochemical staining was performed on the tissue microarray sections, using a panel of markers previously reported to be indicators of intestinal (CDX2, CD10, MUC2) [21][22][23] or gastric (MU-C5AC, MUC6) [23][24][25][26] phenotype. Nuclear b-catenin and MUC1 expression-previously reported to be prognostic biomarkers for adenocarcinomas of the stomach and esophagus 27-29 -was also evaluated.…”

REG4 is associated with carcinogenesis in the ‘intestinal’ pathway of intraductal papillary mucinous neoplasms

“…CDX2 is a transcriptional factor that is important for the maintenance of intestinal identity. 29 MUC2, on the other hand, is a major mucin detected in intestinal epithelium. Considering these findings, REG4 is significantly related with the intestinal phenotype and its expression may be regulated by CDX2.…”