Establishment of Intestinal Identity and Epithelial-Mesenchymal Signaling by Cdx2

Abstract

SUMMARY We demonstrate that conditional ablation of the homeobox transcription factor Cdx2 from early endoderm results in the replacement of the posterior intestinal epithelium with keratinocytes, a dramatic cell fate conversion caused by ectopic activation of the foregut/esophageal differentiation program. This anterior homeotic transformation is first evident in the early embryonic Cdx2-deficient gut as expression of several key foregut endoderm regulators was shifted caudally. While the intestinal transcriptome was severely affected, Cdx2-deficiency only transiently modified selected posterior Hox genes and the primary enteric Hox code was maintained. Further, we demonstrate that Cdx2-directed intestinal cell fate adoption plays an important role in the establishment of normal epithelial-mesenchymal interactions, as multiple signaling pathways involved in this process were severely affected. We conclude that Cdx2 controls important aspects of intestinal identity and development, and that this function is largely independent of the enteric Hox code.

Genome-wide Analysis of CDX2 Binding in Intestinal Epithelial Cells (Caco-2)

“…This list includes several known CDX2 target genes including the HOX genes (30,39), which are known to function downstream of CDX2 in the molecular pathway that establishes the anteroposterior axis during development. The list also excluded some of the known CDX2 targets; this is a consequence of the procedure performed on the data by the CisGenome program.…”

“…The role of CDX1 has been controversial with regard to tumor development, but recent results indicate that CDX1 is dispensable for normal gut development and with only a limited effect on intestinal cancer (46). The expression of CDX1 has previously been shown to be affected by CDX2, and a putative CDX2 binding site was identified in the 5Ј end (30). According to the ChIP-seq results, a second CDX2 binding site is potentially located in an enhancer element in the 3Ј end of the CDX1 gene.…”

“…Furthermore, we have previously shown that HFN4␣ regulates the expression of CDX2; thus, a loop that is necessary for the initiation and completion of differentiation of intestinal cells appears to exist (12). The promoter of HNF4␣ has previously been shown to contain a functional CDX2 binding site (30). In this work we analyzed the promoter along with two novel CDX2 binding sites in a 3Ј end enhancer element.…”

“…The heterozygotic Cdx2 ϩ/Ϫ mice show an increased susceptibility for tumors, underlining the important role of Cdx2 in proliferation and differentiation. A recent study used conditional Cdx2 knock-out mice to confirm the essential role of Cdx2 in intestinal development and furthermore showed that Cdx2 is a key regulator of several transcription factors involved in intestinal development (30).…”

Gene regulatory mechanisms underlying the intestinal innate immune response

“…Among them, CDX2 might be the most important as it is essential for the specification of all intestinal epithelia during mouse endoderm development [43] and required for epithelial cell identity in the adult [44]. CDX2 binds to many regions marked with H3K4me2, a modification associated which enhancers and promoters.…”