Small-scale siRNA screen reveals WWC2 as a novel regulator of cardiomyocyte mitosis.

(145): Adult cardiomyocytes exit the cell cycle soon after birth, although this shift can be reversed by molecular interventions. To identify novel regulators of cardiomyocyte proliferation, we performed a comparative transcriptomic analysis of actively proliferating and non-proliferating cardiomyocytes across key pre-and post-natal developmental timepoints. Integration of bioinformatics analyses with a functional screen of 238 differentially expressed genes identified WWC2 as a regulator of cell cycle exit. Inhibition of Wwc2 induced cell cycle entry with completion of mitosis and cytokinesis, while overexpression of WWC2 induced cell cycle exit. Moreover, inhibition of Wwc2 resulted in dedifferentiation of cardiomyocytes with reduced expression of sarcomeric and calcium handling genes. Mechanistically, WWC2 binds to 14-3-3 and regulates YAP phosphorylation and expression. In vivo, deletion of Wwc2 stimulated cardiac regeneration after myocardial infarction. These results identify WWC2 as an important regulator of cardiomyocyte cell cycle exit and initiation of the maturation process.