The study by Pinto et al. investigates the critical role of canonical Wnt signals in maintaining the homeostasis of the intestinal epithelium. They generated transgenic mice expressing Dickkopf1 (Dkk1), a secreted Wnt inhibitor, to block Wnt signaling. The results show that Dkk1 expression leads to a significant reduction in epithelial proliferation and the loss of crypts, with enterocyte differentiation appearing unaffected but secretory cell lineages largely absent. The disrupted intestinal homeostasis is reflected by the absence of nuclear β-catenin, inhibition of c-myc expression, and up-regulation of p21CIP1/WAF1. This work establishes a direct requirement for Wnt ligands in driving proliferation in the intestinal epithelium and defines an unexpected role for Wnts in controlling secretory cell differentiation. The findings also highlight the importance of Wnt signaling in regulating the proliferation-differentiation switch in the intestinal epithelium.The study by Pinto et al. investigates the critical role of canonical Wnt signals in maintaining the homeostasis of the intestinal epithelium. They generated transgenic mice expressing Dickkopf1 (Dkk1), a secreted Wnt inhibitor, to block Wnt signaling. The results show that Dkk1 expression leads to a significant reduction in epithelial proliferation and the loss of crypts, with enterocyte differentiation appearing unaffected but secretory cell lineages largely absent. The disrupted intestinal homeostasis is reflected by the absence of nuclear β-catenin, inhibition of c-myc expression, and up-regulation of p21CIP1/WAF1. This work establishes a direct requirement for Wnt ligands in driving proliferation in the intestinal epithelium and defines an unexpected role for Wnts in controlling secretory cell differentiation. The findings also highlight the importance of Wnt signaling in regulating the proliferation-differentiation switch in the intestinal epithelium.