1. Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands
2. These authors contributed equally to this work

Correspondence to: Hans Clevers¹ Email: clevers@niob.knaw.nl

Abstract

Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/-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 -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 -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/-catenin signalling in determining endocardial cell fate.