Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Researchers investigated the role of Wnt signals in intestinal crypts by generating transgenic mice expressing Dickkopf1 (Dkk1), a secreted Wnt inhibitor. They found that epithelial proliferation was greatly reduced, with secretory cell lineages largely absent. Disrupted intestinal homeostasis was reflected by the absence of nuclear β-catenin, inhibition of c-myc expression, and up-regulation of p21. These findings establish a direct requirement for Wnt ligands in driving proliferation in the intestinal epithelium and define an unexpected role for Wnts in controlling secretory cell differentiation. Wnt signaling is initiated by binding of secreted Wnt glycoproteins to their transmembrane coreceptors, Frizzled proteins and LRP5/6. The Wnt-Fz-LRP5/6 complex transmits a signal into the cell, resulting in nuclear accumulation of β-catenin and activation of TCF target genes. Dkk1 inhibits this complex formation. Previous studies suggest that Wnt signals regulate intestinal stem cell proliferation. However, they do not provide evidence for the requirement of Wnt signals in intestinal proliferation. The study found that Dkk1 expression led to morphological alterations in the intestinal epithelium, including disorganized mucosa and shortened villi. Immunohistochemistry revealed that Dkk1 expression affected Paneth cell allocation, indicating that canonical Wnt signaling is essential for their positioning. The study also showed that Dkk1 expression inhibited proliferation, leading to the loss of crypts and the absence of nuclear β-catenin. This suggested that the loss of canonical Wnt signaling was responsible for the observed intestinal phenotype. The study further demonstrated that Dkk1 expression affected the expression of β-catenin target genes, such as Enc-1 and alkaline phosphatase (AP), indicating that Wnt signaling is required for the differentiation of secretory cell types. The study also showed that the Wnt/β-catenin pathway is essential for the maintenance of Math1-positive progenitors for the secretory cell lineage. The findings highlight the critical importance of canonical Wnt signals in the homeostasis of the intestinal epithelium. The study provides in vivo evidence for the opposing roles of c-Myc and p21 in regulating the proliferation-differentiation switch in the intestinal epithelium. The study also reveals an unexpected increased requirement of secretory cell progenitors for canonical Wnt signaling compared with enterocyte progenitors.Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Researchers investigated the role of Wnt signals in intestinal crypts by generating transgenic mice expressing Dickkopf1 (Dkk1), a secreted Wnt inhibitor. They found that epithelial proliferation was greatly reduced, with secretory cell lineages largely absent. Disrupted intestinal homeostasis was reflected by the absence of nuclear β-catenin, inhibition of c-myc expression, and up-regulation of p21. These findings establish a direct requirement for Wnt ligands in driving proliferation in the intestinal epithelium and define an unexpected role for Wnts in controlling secretory cell differentiation. Wnt signaling is initiated by binding of secreted Wnt glycoproteins to their transmembrane coreceptors, Frizzled proteins and LRP5/6. The Wnt-Fz-LRP5/6 complex transmits a signal into the cell, resulting in nuclear accumulation of β-catenin and activation of TCF target genes. Dkk1 inhibits this complex formation. Previous studies suggest that Wnt signals regulate intestinal stem cell proliferation. However, they do not provide evidence for the requirement of Wnt signals in intestinal proliferation. The study found that Dkk1 expression led to morphological alterations in the intestinal epithelium, including disorganized mucosa and shortened villi. Immunohistochemistry revealed that Dkk1 expression affected Paneth cell allocation, indicating that canonical Wnt signaling is essential for their positioning. The study also showed that Dkk1 expression inhibited proliferation, leading to the loss of crypts and the absence of nuclear β-catenin. This suggested that the loss of canonical Wnt signaling was responsible for the observed intestinal phenotype. The study further demonstrated that Dkk1 expression affected the expression of β-catenin target genes, such as Enc-1 and alkaline phosphatase (AP), indicating that Wnt signaling is required for the differentiation of secretory cell types. The study also showed that the Wnt/β-catenin pathway is essential for the maintenance of Math1-positive progenitors for the secretory cell lineage. The findings highlight the critical importance of canonical Wnt signals in the homeostasis of the intestinal epithelium. The study provides in vivo evidence for the opposing roles of c-Myc and p21 in regulating the proliferation-differentiation switch in the intestinal epithelium. The study also reveals an unexpected increased requirement of secretory cell progenitors for canonical Wnt signaling compared with enterocyte progenitors.