Wt1 at the heart of cell fate determination

The vertebrate heart is made up of three layers: the endocardium, myocardium and epicardium. Proper epicardial differentiation is dependent on the Wilms tumour 1 (Wt1) transcription factor, which is expressed in proepicardial and epicardial cells during embryonic development. Using the zebrafish model, Ines Marques, Nadia Mercader and colleagues now show that Wt1 needs to be actively repressed in myocardial progenitors to prevent their differentiation to an epicardial-like fate. The authors demonstrate the existence of a Wt1-positive progenitor pool that gives rise to both epicardial and myocardial cells; in the cardiomyocyte population, the Wt1 locus becomes decorated with repressive histone marks, presumably leading to its silencing. Overexpression of Wt1 in developing cardiomyocytes leads to loss of expression of cardiomyocyte markers and gain of epicardial marker gene expression – suggesting a fate switch in these cells. Moreover, these cells delaminate from the myocardial layer and integrate into the epicardium. This cellular phenotype is associated with changes in the expression and localisation of junctional and apicobasal polarity proteins. Functionally, the hearts of zebrafish overexpressing Wt1 in cardiomyocyte progenitors show impaired cardiac function, demonstrating the crucial importance of Wt1 downregulation in the myocardial lineage for heart development.