WT1 transcription factor impairs cardiomyocyte specification and drives a phenotypic switch from myocardium to epicardium.

Abstract

During development, the heart growths through addition of progenitor cells to the poles of the primordial heart tube. In the zebrafish, wilms tumor 1 transcription factor a (wt1a) and b (wt1b) are expressed in the pericardium, at the venous pole of the heart. From this pericardial layer, the proepicardium emerges. Proepicardial cells are subsequently transferred to the myocardial surface and form the epicardium, covering the myocardium. We found that while wt1a/b expression is maintained in proepicardial cells, it is downregulated in those pericardial cells contributing to cardiomyocytes from the developing heart. Sustained wt1 expression in cardiomyocytes reduced chromatin accessibility of specific genomic loci. Strikingly, a subset of wt1a/b-expressing cardiomyocytes changed their cell adhesion properties, delaminated from the myocardium and upregulated epicardial gene expression. Thus, wt1 acts as a break for cardiomyocyte differentiation and ectopic wt1 expression in cardiomyocytes can lead to their transdifferentiation into epicardial like cells.