Summary During embryogenesis, distinct cardiac cell types form, which shape the structural and functional properties of the heart. How their activity is coordinated is largely unknown. Here we show that Rnf20 is a multifaceted regulator of cardiac morphogenesis and function. On the one hand, Rnf20 controls extracellular matrix dynamics and endothelial-cardiomyocyte crosstalk essential for second heart field development. On the other hand, it safeguards endothelial cell identity and function by maintaining physiological angiocrine signaling and preventing endothelial-to-mesenchymal transition. Endothelial-specific deletion of Rnf20 led to ventricular septal defects, myocardial thinning and cardiac dysfunction as a result of aberrant signaling and excessive extracellular matrix deposition that induced precocious cardiomyocyte binucleation and irregular contractility. Furthermore, we uncovered upstream factors (e.g. Sox9) and multiple angiocrine and extracellular matrix molecules that alter cardiomyocyte functionality upon endothelial Rnf20 loss. In summary, our work identifies a novel, endothelial-specific role of Rnf20 in regulating cardiac morphogenesis and function.

Rnf20 shapes the endothelial control of heart morphogenesis and function