Cdx function is required for maintenance of intestinal identity in the adult

Abstract

The homeodomain transcription factors Cdx1 and Cdx2 are expressed in the intestinal epithelium from early development, with expression persisting throughout the life of the animal. While our understanding of the function of Cdx members in intestinal development has advanced significantly, their roles in the adult intestine is relatively poorly understood. In the present study, we found that ablation of Cdx2 in the adult small intestine severely impacted villus morphology, proliferation and intestinal gene expression patterns, resulting in the demise of the animal. Long-term loss of Cdx2 in a chimeric model resulted in loss of all differentiated intestinal cell types and partial conversion of the mucosa to a gastric-like epithelium. Concomitant loss of Cdx1 did not exacerbate any of these phenotypes. Loss of Cdx2 in the colon was associated with a shift to a cecum-like epithelial morphology and gain of cecum-associated genes which was more pronounced with subsequent loss of Cdx1. These findings suggest that Cdx2 is essential for differentiation of the small intestinal epithelium, and that both Cdx1 and Cdx2 contribute to homeostasis of the colon.

Ketogenesis contributes to intestinal cell differentiation

“…40 Ablation of Cdx2 in the intestine results in a decrease of mature enterocytes, and loss of goblet, enteroendocrine and Paneth cells. 41 We showed that treatment with βHB or overexpression of ketogenic enzyme HMGCS2 increased CDX2 expression in intestinal cells. Moreover, our results showed that increased ketogenesis resulted in increased CDX2 expression along with increased differentiation in the intestinal epithelium of mice.…”

Cdx2 Regulates Gene Expression through Recruitment of Brg1-associated Switch-Sucrose Non-fermentable (SWI-SNF) Chromatin Remodeling Activity

“…Cdx and Brg1 Interact in Vivo-Cdx and SWI-SNF impact intestinal differentiation programs and are required for maintenance of the intestinal stem cell niche (7,11,44). To determine whether Cdx and Brg1 interacted genetically in this context, we assessed intestinal cell differentiation using differential staining for enterocytes and goblet and enteroendocrine cells, comparing control Cdx1 (Fig.…”

“…In the mouse, the three members of this family (Cdx1, Cdx2, and Cdx4) are co-expressed in the caudal embryo in all three germ layers commencing at mid-gastrulation and play overlapping roles in a number of developmental programs, including axial elongation, endoderm specification, and anterior-posterior vertebral patterning (1)(2)(3)(4)(5)(6). Both Cdx1 and Cdx2 are also expressed in the intestinal epithelium throughout life, where they play critical roles in intestinal homeostasis (7)(8)(9)(10)(11) and can function as tumor suppressors (12)(13)(14)(15). Although Cdx members play critical roles in governing gene expression during development and in the adult intestine, little is known about the mechanisms by which Cdx members regulate target gene transcription.…”

Transcription Factors GATA4 and HNF4A Control Distinct Aspects of Intestinal Homeostasis in Conjunction with Transcription Factor CDX2

“…CDX2 is required for proper specification of the intestine during development (8) and is considered a master regulator of intestinal identity because its ectopic expression in the stomach or esophagus activates intestine-restricted genes (9,10). In adult mice, absence of CDX2 dysregulates genes involved in terminal cell differentiation, and fatal malnutrition ensues over ϳ3 weeks (11)(12)(13). Simultaneous inactivation of its homolog CDX1 results in nearly complete arrest of intestinal crypt cell proliferation (14).…”