The Wnt/β-catenin pathway regulates cardiac valve formation

Adam F. L. Hurlstone, Anna-Pavlina G. Haramis, Erno Wienholds, Harry Begthel, Jeroen Korving, Fredericus van Eeden, Edwin Cuppen, Danica Zivkovic, Ronald H. A. Plasterk and Hans Clevers ()
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Adam F. L. Hurlstone: Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics
Anna-Pavlina G. Haramis: Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics
Erno Wienholds: Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics
Harry Begthel: Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics
Jeroen Korving: Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics
Fredericus van Eeden: Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics
Edwin Cuppen: Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics
Danica Zivkovic: Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics
Ronald H. A. Plasterk: Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics
Hans Clevers: Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics

Nature, 2003, vol. 425, issue 6958, 633-637

Abstract: Abstract Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/β-catenin signalling pathway1. Apc has a role in development: for example, embryos of mice with truncated Apc do not complete gastrulation2. 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 inhibitor3, blocks cushion formation. In wild-type hearts, nuclear β-catenin, the hallmark of activated canonical Wnt signalling4, 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.

Date: 2003
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DOI: 10.1038/nature02028

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