A homeodomain protein related to caudal regulates intestine-specific gene transcription.

Abstract

The continually renewing epithelium of the intestinal tract arises from the visceral endoderm by a series of complex developmental transitions. The mechanisms that establish and maintain the processes of cellular renewal, cell lineage allocation, and tissue restriction and spatial assignment of gene expression in this epithelium are unknown. An understanding of the regulation of intestine-specific gene regulation may provide information on the molecular mechanisms that direct these processes. In this regard, we show that intestine-specific transcription of sucrase-isomaltase, a gene that is expressed exclusively in differentiated enterocytes, is dependent on binding of a tissue-specific homeodomain protein (mouse Cdx-2) to an evolutionarily conserved promoter element in the sucrase-isomaltase gene. This protein is a member of the caudal family of homeodomain genes which appear to function in early developmental events in Drosophila melanogaster, during gastrulation in many species, and in intestinal endoderm. Unique for this homeodomain gene family, we show that mouse Cdx-2 binds as a dimer to its regulatory element and that dimerization in vitro is dependent on redox potential. These characteristics of the interaction of Cdx-2 with its regulatory element provide for a number of potential mechanisms for transcriptional regulation. Taken together, these findings suggest that members of the Cdx gene family play a fundamental role both in the establishment of the intestinal phenotype during development and in maintenance of this phenotype via transcriptional activation of differentiated intestinal genes.The epithelium of the intestinal tract arises from the visceral endoderm by progression through a series of developmental transitions (reviewed in references 33, 34, and 42). The early signals for intestinal development have been shown to be partially directed by the interaction of mesoderm with endoderm, although the mechanism of this effect has not been elucidated (reviewed in references 23 and 24). Later events include the emergence of different epithelial cell lineages, formation of crypts (proliferative compartment) and villi (differentiated compartment), and the coordinated expression of cell-specific genes. The resultant mature epithelia of the small intestine and colon have marked regional differences in architecture, cell populations, and gene expression which define distinct functional zones of the adult gut (reviewed in references 20, 21, and 50). These region-specific phenotypes are maintained throughout the life of the animal. The regulatory mechanisms that orchestrate these complex developmental transitions and maintain the well-ordered regional phenotypes along the cephalocaudal and crypt-villus axes have not been defined.

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

“…In our datasets, we observe strong correlation between loss of CDX2 and the CMS1 and CMS4 subtypes, in accordance with the strong association of CDX2 loss with MSI (CMS1) and worse prognosis (CMS4), and loss of differentiation, a hallmark of CDX2 loss in cancer (Suh et al ., 1994). In contrast to a recent study (Pilati et al ., 2017), we showed that loss of CDX2 is associated with shorter survival in both CMS1 and CMS4.…”

Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett's) metaplasia

“…Human Cdx2 is a member of the caudalrelated homeobox gene family that activates an intestinal-specific gene transcription, which regulates normal intestinal development and differentiation and plays an important role in triggering cells towards the phenotype of differentiated enterocytes as well as in the maintenance of the phenotype. [15][16][17][18][19] Cdx2 expression in normal adult tissues is restricted to intestinal and colonic epithelium and a subset of pancreatic acinar and ductal cells. 22,24,27 In neoplasms, it is expressed by small and large intestinal epithelial tumors, by esophageal, urinary bladder and ovarian mucinous adenocarcinomas, and by a subset of pancreatobiliary adenocarcinomas.…”

“…[15][16][17][18][19] The expression of Cdx2 in adult non-neoplastic tissues has been shown to be restricted to normal intestinal epithelium, normal pancreatic epithelial cells, and gastric and esophageal intestinal metaplasia. [20][21][22][23][24][25][26][27] In the gastrointestinal tract, Cdx2 is strongly and diffusely expressed in the nuclei of normal small and large intestinal epithelial cells, including absorptive, goblet, endocrine and Paneth cells; in the pancreatic epithelium its expression is focal and patchy.…”

The intestine-specific homeobox gene Cdx2 decreases mobility and antagonizes dissemination of colon cancer cells

“…The sucrase-isomaltase and LI-cadherin genes, downregulated in migrating cells of the wound edge, are direct targets of the transcription factor Cdx2 (Suh et al, 1994;Hinoi et al, 2002). Therefore, we analysed Cdx2 in the wound healing model (Figure 2).…”