Canonical Wnt signals are essential for homeostasis of the intestinal epithelium

To assess the critical role of Writ signals in intestinal crypts, we generated transgenic mice ectopically expressing Dickkopf 1 (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 beta-catenin, inhibition of c-myc expression, and subsequent up-regulation of p21(CIP1/WAF1). Thus, our data are the first to establish a direct requirement for Writ ligands in driving proliferation in the intestinal epithelium, and also define an unexpected role for Writs in controlling secretory cell differentiation.