Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation.
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-beta-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.
van den Brink
Gijs R
GR
Department of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. g.r.vandenbrink@amc.uva.nl
Bleuming
Sylvia A
SA
Hardwick
James C H
JC
Schepman
Berber L
BL
Offerhaus
G Johan
GJ
Keller
Josbert J
JJ
Nielsen
Corinne
C
Gaffield
William
W
van Deventer
Sander J H
SJ
Roberts
Drucilla J
DJ
Peppelenbosch
Maikel P
MP
D011125:Adenomatous Polyposis Coli / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D002454:Cell Differentiation; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D019073:HT29 Cells; D053823:Hedgehog Proteins; D006801:Humans; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D025601:Adenomatous Polyposis Coli Protein; D053823:Hedgehog Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins