TY - JOUR
T1 - The Wnt/β-catenin pathway regulates cardiac valve formation
AU - Hurlstone, Adam F.L.
AU - Haramis, Anna Pavlina G.
AU - Wienholds, Erno
AU - Begthel, Harry
AU - Korving, Jeroen
AU - Van Eeden, Fredericus
AU - Cuppen, Edwin
AU - Zivkovic, Danica
AU - Plasterk, Ronald H.A.
AU - Clevers, Hans
N1 - Funding Information:
Acknowledgements We thank all the BBS families for their willing and continued participation in our studies; J. Sowden, S. Darling and R. Graham for technical help; and J. Lupski, A. Chakravarti, J. Nathans, P. Scambler, A. McCallion and L. Kotch for their critical evaluation of this manuscript. We also thank J. Morton for clinical details and J. Goodship for discussions. This study was supported by grants from the National Institute of Child Health and Development, NIH and the March of Dimes (N.K.), the Research Department of the King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia (J.C.C., R.A.L.), the Foundation Fighting Blindness, USA (R.A.L.), the Research to Prevent Blindness, New York (R.A.L.), NCIC, HSFBC&Y, CIHR and MSFHR (M.R.L.), NSERC (R.C.J.), Genome BC and Genome Canada (R.C.J., K.M.), the National Kidney Research Fund (B.E.H.), the Birth Defects Foundation (P.L.B.), and the Wellcome Trust (P.L.B.).
PY - 2003/10/9
Y1 - 2003/10/9
N2 - Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/β-catenin signalling pathway. Apc has a role in development: for example, embryos of mice with truncated Apc do not complete gastrulation. To understand this role more fully, we examined the effect of truncated Apc on zebrafish development. Here we show that, in contrast to mice, zebrafish do complete gastrulation. However, mutant hearts fail to loop and form excessive endocardial cushions. Conversely, overexpression of Apc or Dickkopf 1 (Dkk1), a secreted Wnt inhibitor, blocks cushion formation. In wild-type hearts, nuclear β-catenin, the hallmark of activated canonical Wnt signalling, accumulates only in valve-forming cells, where it can activate a Tcf reporter. In mutant hearts, all cells display nuclear β-catenin and Tcf reporter activity, while valve markers are markedly upregulated. Concomitantly, proliferation and epithelial-mesenchymal transition, normally restricted to endocardial cushions, occur throughout the endocardium. Our findings identify a novel role for Wnt/β-catenin signalling in determining endocardial cell fate.
AB - Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/β-catenin signalling pathway. Apc has a role in development: for example, embryos of mice with truncated Apc do not complete gastrulation. To understand this role more fully, we examined the effect of truncated Apc on zebrafish development. Here we show that, in contrast to mice, zebrafish do complete gastrulation. However, mutant hearts fail to loop and form excessive endocardial cushions. Conversely, overexpression of Apc or Dickkopf 1 (Dkk1), a secreted Wnt inhibitor, blocks cushion formation. In wild-type hearts, nuclear β-catenin, the hallmark of activated canonical Wnt signalling, accumulates only in valve-forming cells, where it can activate a Tcf reporter. In mutant hearts, all cells display nuclear β-catenin and Tcf reporter activity, while valve markers are markedly upregulated. Concomitantly, proliferation and epithelial-mesenchymal transition, normally restricted to endocardial cushions, occur throughout the endocardium. Our findings identify a novel role for Wnt/β-catenin signalling in determining endocardial cell fate.
UR - http://www.scopus.com/inward/record.url?scp=0142136734&partnerID=8YFLogxK
U2 - 10.1038/nature02028
DO - 10.1038/nature02028
M3 - Article
C2 - 14534590
AN - SCOPUS:0142136734
SN - 0028-0836
VL - 425
SP - 633
EP - 637
JO - Nature
JF - Nature
IS - 6958
ER -