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The Wnt/β-catenin pathway regulates cardiac valve formation

Nature volume 425, pages 633–637 (2003)Cite this article

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.

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Figure 1: Mutation of apc results in heart malformation.
Figure 2: Wnt/β-catenin signalling regulates endocardial cushion formation.
Figure 3: Deregulated Wnt/β-catenin signalling and proliferation in apc mutant hearts.
Figure 4: Expression of valve markers is upregulated and expanded in apc hearts.

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Acknowledgements

We thank R. Dorsky and R. Moon for TOPdGFP fish and the APC–GFP construct; M. Kosters and J. Mudde for library screening; and J. Bakkers, M. Morkel and W. Birchmeier for sharing reagents and observations before publication.

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  1. Adam F. L. Hurlstone and Anna-Pavlina G. Haramis: These authors contributed equally to this work

Authors and Affiliations

  1. Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands

    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 & Hans Clevers

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  1. Adam F. L. Hurlstone
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Correspondence to Hans Clevers.

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Hurlstone, A., Haramis, AP., Wienholds, E. et al. The Wnt/β-catenin pathway regulates cardiac valve formation. Nature 425, 633–637 (2003). https://doi.org/10.1038/nature02028

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