Canonical Wnt signals are essential for homeostasis of the intestinal epithelium

Abstract

To assess the critical role of Wnt signals in intestinal crypts, we generated transgenic mice ectopically expressing Dickkopf1 (Dkk1), a secreted Wnt inhibitor. We find that epithelial proliferation is greatly reduced coincidentally with the loss of crypts. Although enterocyte differentiation appears unaffected, secretory cell lineages are largely absent. Disrupted intestinal homeostasis is reflected by an absence of nuclear ␤-catenin, inhibition of c-myc expression, and subsequent up-regulation of p21. Thus, our data are the first to establish a direct requirement for Wnt ligands in driving proliferation in the intestinal epithelium, and also define an unexpected role for Wnts in controlling secretory cell differentiation.Supplemental material is available at http://www.genesdev.org.

Carcinogenesis in Mouse Stomach by Simultaneous Activation of the Wnt Signaling and Prostaglandin E2 Pathway

“…Wnt signaling plays an important role in the maintenance of the intestinal crypt containing the stem cells and undifferentiated progenitor cells 14,15 . In the gastric gland, Wnt signaling also keeps the progenitor cells undifferentiated in the isthmus of the gastric gland, as we have shown that the number of progenitors increased significantly in the K19-Wnt1 mouse stomach.…”

“…Given that Wnt signaling is essential for maintaining the intestinal crypt that contains epithelial progenitor cells and stem cells 14,15 , we examined gastric epithelial differentiation in the K19-Wnt1 mice. The trefoil factor 2 (TFF2) was used as an undifferentiated epithelial marker, because it was detected in the small isthmal cells ( Figure 3A and B) where β-catenin accumulated in both the nucleus and cytoplasm ( Figure 3C).…”

Wnt signaling in disease and in development

“…In the colon, loss of TCF4 or Dkk over-expression promotes loss of stem cells in the colon crypt, indicating that Wnt signaling is required for maintenance of the stem cell compartment [40][41][42]. Wnt signaling may therefore be a fundamental regulator of stem cell choices to proliferate or self-renew.…”

Role of Pinin in neural crest, dorsal dermis, and axial skeleton development and its involvement in the regulation of Tcf/Lef activity in mice

“…Wnt/␤-catenin signaling has been implicated in a variety of physiological and pathological processes, including epithelial-mesenchymal transition (EMT), cell fate specification, embryonic induction, stem cell homeostasis, and tumorigenesis (Korinek et al, 1997;Maretto et al, 2003;Pinto et al, 2003;Sato et al, 2004;Willert and Jones, 2006). Canonical Wnt signaling leads to cytoplasmic accumulation of hypophosphorylated ␤-catenin, which in turn translocates into the nucleus, interacts with T-cell factor (TCF)/lymphoid enhancer factor (LEF), and regulates expression of diverse Wnt target genes (Korinek et al, 1997;Schmidt and Patel, 2005).…”