Canonical Wnt signals are essential for homeostasis of the intestinal epithelium.
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 beta-catenin, inhibition of c-myc expression, and subsequent up-regulation of p21CIP1/WAF1. 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.
Pinto
Daniel
D
Netherlands Institute for Developmental Biology, Hubrecht Laboratory, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Gregorieff
Alex
A
Begthel
Harry
H
Clevers
Hans
H
D000818:Animals; D002455:Cell Division / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C501128:dkk1b protein, zebrafish