Ruvbl2 Suppresses Cardiomyocyte Proliferation During Zebrafish Heart Development and Regeneration.

Cardiomyocyte proliferation is an important source of new myocardium during heart development and regeneration. Consequently, mutations in drivers of cardiomyocyte proliferation cause congenital heart disease, and infarcted human hearts scar because cardiomyocytes exit the cell cycle postnatally. To boost cardiomyocyte proliferation in either setting, critical regulators must be identified. Through an ENU screen in zebrafish, the () mutant was isolated and described as having elevated cardiomyocyte numbers during embryogenesis. The mutation results in a three amino acid insertion into Ruvbl2, a highly conserved ATPase. Because both gain- and loss-of-function properties have been described for , it remains unclear whether Ruvbl2 positively or negatively regulates cardiomyocyte proliferation. Here, we demonstrate that Ruvbl2 is a suppressor of cardiomyocyte proliferation during zebrafish heart development and regeneration. First, we confirmed speculation that augmented cardiomyocyte numbers in hearts arise by hyperproliferation. To characterize bona fide null animals, we created a locus deletion allele ( ). Like mutants, and compound heterozygote animals display ventricular hyperplasia, demonstrating that is a loss of function allele and that represses cardiomyocyte proliferation. This activity is autonomous because constitutive myocardial overexpression of Ruvbl2 is sufficient to suppress cardiomyocyte proliferation in control hearts and rescue the hyperproliferation observed in mutant hearts. Lastly, heat-shock inducible overexpression of Ruvbl2 suppresses cardiomyocyte proliferation during heart regeneration and leads to scarring. Together, our data demonstrate that Ruvbl2 functions autonomously as a suppressor of cardiomyocyte proliferation during both zebrafish heart development and adult heart regeneration.