Cdx2 regulates patterning of the intestinal epithelium

Abstract

Cdx1, Cdx2 and Cdx4 encode homeodomain transcription factors that are involved in vertebral anterior-posterior (AP) patterning. Cdx1 and Cdx2 are also expressed in the intestinal epithelium during development, suggesting a role in this tissue. Intestinal defects have not been reported in Cdx1 null mutants, while Cdx2 null mutants die at embryonic day 3.5 (E3.5), thus precluding assessment of the null phenotype at later stages. To circumvent this latter shortcoming, we have used a conditional Cre-lox strategy to inactivate Cdx2 in the intestinal epithelium. Using this approach, we found that ablation of Cdx2 at E13.5 led to a transformation of the small intestine to a pyloric stomach-like identity, although the molecular nature of the underlying mesenchyme remained unchanged. Further analysis of Cdx1-Cdx2 double mutants suggests that Cdx1 does not play a critical role in the development of the small intestine, at least after E13.5.

Concerted involvement of Cdx/Hox genes and Wnt signaling in morphogenesis of the caudal neural tube and cloacal derivatives from the posterior growth zone

“…Another study (Gao and Kaestner, 2010) also reported that Cdx2-null embryos exhibit multiple lumens, with disturbed apico-basal polarity in the endoderm epithelium. Abnormal apicobasal position of nuclei in Cdx2 mutant intestinal epithelium has also been described (Grainger et al, 2010), which resembles the irregular polarization of the neurectoderm in Cdx mutants described here.…”

“…Furthermore, it is unlikely that Cdx involvement in anorectal development is exerted at the level of the endoderm. Grainger and colleagues (Grainger et al, 2010) report that endoderm-specific inactivation of Cdx2 using the VillinP-Cre does not lead to imperforate anus. These data, together with our observations on the Wnt3a mutant phenotype, the TPLef1 rescue of 3457 RESEARCH ARTICLE Cdx in posterior development Cdx mutants and the growth zone-restricted expression of the canonical Wnt pathway components, emphasize an essential role of the Cdx and Wnt at the level of the posterior growth zone that supplies progenitors for the cloacal structures earlier than uro-rectal septum generation (see graph in Fig.…”

The Parahox gene Pdx1 is required to maintain positional identity in the adult foregut

“…The Parahox genes Pdx1 and Cdx2 are predominantly expressed Evidence of a homeotic role for Cdx2 has been deduced from the phenotype of Cdx2 heterozygous mice, which exhibit skeletal defects consistent with an anterior homeotic shift and hamartomatous polyps that arise from ectopic foci of gastric tissue in the colon (Beck et al, 1999;Chawengsaksophak et al et al, 1999). This role is further supported by experiments in which ectopic expression of Cdx2 in the gastric epithelium leads to intestinal (posterior) transformation while conditional inactivation of Cdx2 in the hindgut results in anterior transformation of the posterior gut (Gao et al, 2009;Grainger et al, 2010). Similarly, ectopic expression of Pdx1 outside its native domain in the emanteriorly (Sox2) or posteriorly (Cdx2) (Grapin-Botton et al, 2001;Silberg et al, 2002).…”

Stomach development, stem cells and disease

“…This suggests the presence of a common foregut progenitor cell pool and highlights that few if any regionally restricted TFs function exclusively in stomach development. Thus, whereas Cdx2, which is required for intestine specification (Gao et al, 2009;Grainger et al, 2010), is expressed selectively in the prospective mouse intestine, Sox2 levels are high in embryonic esophageal and stomach epithelia, and reduced Sox2 levels lead to defective differentiation of both tissues (Que et al, 2009). Conversely, ectopic Sox2 expression in the mouse intestinal epithelium causes defective intestinal differentiation with activation of some gastric markers (Raghoebir et al, 2012), while forced Cdx2 expression in the mouse stomach endoderm induces intestinal differentiation (Silberg et al, 2002).…”