TY - JOUR
T1 - Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation
AU - Van Den Brink, Gijs R.
AU - Bleuming, Sylvia A.
AU - Hardwick, James C.H.
AU - Schepman, Berber L.
AU - Offerhaus, G. Johan
AU - Keller, Josbert J.
AU - Nielsen, Corinne
AU - Gaffield, William
AU - Van Deventer, Sander J.H.
AU - Roberts, Drucilla J.
AU - Peppelenbosch, Maikel P.
PY - 2004/3/1
Y1 - 2004/3/1
N2 - Wnt signaling defines the colonic epithelial progenitor cell phenotype, and mutations in the gene adenomatous polyposis coli (APC) that activate the Wnt pathway cause the familial adenomatous polyposis coli (FAP) syndrome and most sporadic colon cancers. The mechanisms that regulate the transition of epithelial precursor cells into their differentiated derivatives are poorly characterized. We report that Indian hedgehog (Ihh) is expressed by mature colonocytes and regulates their differentiation in vitro and in vivo. Hedgehog (Hh) signaling restricts the expression of Wnt targets to the base of the colonic crypt in vivo, and transfection of Ihh into colon cancer cells leads to a downregulation of both components of the nuclear TCF4-β-catenin complex and abrogates endogenous Wnt signaling in vitro. In turn, expression of Ihh is downregulated in polyps of individuals with FAP and expression of doxycycline-inducible dominant negative TCF4 (dnTCF4) restores Ihh expression in APC mutant DLD-1 colon cancer cells. These data identify a new Wnt-Hh axis in colonic epithelial renewal.
AB - Wnt signaling defines the colonic epithelial progenitor cell phenotype, and mutations in the gene adenomatous polyposis coli (APC) that activate the Wnt pathway cause the familial adenomatous polyposis coli (FAP) syndrome and most sporadic colon cancers. The mechanisms that regulate the transition of epithelial precursor cells into their differentiated derivatives are poorly characterized. We report that Indian hedgehog (Ihh) is expressed by mature colonocytes and regulates their differentiation in vitro and in vivo. Hedgehog (Hh) signaling restricts the expression of Wnt targets to the base of the colonic crypt in vivo, and transfection of Ihh into colon cancer cells leads to a downregulation of both components of the nuclear TCF4-β-catenin complex and abrogates endogenous Wnt signaling in vitro. In turn, expression of Ihh is downregulated in polyps of individuals with FAP and expression of doxycycline-inducible dominant negative TCF4 (dnTCF4) restores Ihh expression in APC mutant DLD-1 colon cancer cells. These data identify a new Wnt-Hh axis in colonic epithelial renewal.
UR - http://www.scopus.com/inward/record.url?scp=10744233571&partnerID=8YFLogxK
U2 - 10.1038/ng1304
DO - 10.1038/ng1304
M3 - Article
C2 - 14770182
AN - SCOPUS:10744233571
SN - 1061-4036
VL - 36
SP - 277
EP - 282
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -