Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1.
Whereas the adult gastrointestinal epithelium undergoes tremendous self-renewal through active proliferation in crypt stem cell compartments, the responsible growth factors regulating this continuous proliferation have not been defined. The exploration of physiologic functions of Wnt proteins in adult organisms has been hampered by functional redundancy and the necessity for conditional inactivation strategies. Dickkopf-1 (Dkk1) is a potent secreted Wnt antagonist that interacts with Wnt coreceptors of the LRP family. To address the contribution of Wnt signaling to gastrointestinal epithelial proliferation, adenoviral expression of Dkk1 was used to achieve stringent, conditional, and reversible Wnt inhibition in adult animals. Adenovirus Dkk1 (Ad Dkk1) treatment of adult mice repressed expression of the Wnt target genes CD44 and EphB2 within 2 days in both small intestine and colon, indicating an extremely broad role for Wnt signaling in the maintenance of adult gastrointestinal gene expression. In parallel, Ad Dkk1 markedly inhibited proliferation in small intestine and colon, accompanied by progressive architectural degeneration with the loss of crypts, villi, and glandular structure by 7 days. Whereas decreased Dkk1 expression at later time points (>10 days) was followed by crypt and villus regeneration, which was consistent with a reversible process, substantial mortality ensued from colitis and systemic infection. These results indicate the efficacy of systemic expression of secreted Wnt antagonists as a general strategy for conditional inactivation of Wnt signaling in adult organisms and illustrate a striking reliance on a single growth factor pathway for the maintenance of the architecture of the adult small intestine and colon.
Kuhnert
Frank
F
Department of Medicine, Stanford University School of Medicine, Center for Clinical Sciences Research 3100, 269 Campus Drive, Stanford, CA 94305, USA.
Davis
Corrine R
CR
Wang
Hsiao-Ting
HT
Chu
Pauline
P
Lee
Mark
M
Yuan
Jenny
J
Nusse
Roel
R
Kuo
Calvin J
CJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division; D003106:Colon / Q000166:cytology* / Q000378:metabolism*; D015870:Gene Expression; D005822:Genetic Vectors; D018960:Hyaluronan Receptors / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D007421:Intestine, Small / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics* / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D036183:Receptor, EphB2 / Q000235:genetics; D015398:Signal Transduction; D051153:Wnt Proteins; D029961:Zebrafish Proteins
C501127:Dkk1 protein, mouse; D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C501128:dkk1b protein, zebrafish; D036183:Receptor, EphB2