M. Leone, N. Kinz, F. Eichin, D. Obwegs, V. C. Sladky, V. Z. Braun, R. Hirschberger, D. Rizzotto, L. Englmaier, C. Manzl, K. Moos, J. Mergner, P. Giansanti, N. Martinez-Garcia, M. M. Marques, E. D. Jacotot, L. Eblahed, R. Yousif, M. K. Wright, D. Dawood, L. S. Maupome, C. Savko, M. Boerries, M. A. Sussman, A. Villunger
The adult mammalian heart is characterized by post-mitotic polyploid cardiomyocytes (CMs). Understanding how CMs regulate cell cycle exit and polyploidy can help developing new heart regenerative therapies. Here, we uncover that the PIDDosome, a multi-protein complex activating the endopeptidase Caspase-2, helps to implement a CM-specific differentiation program that limits ploidy during postnatal heart development. DNA content analyses show that cell-autonomous PIDDosome loss causes an increase in nuclear and cellular CM ploidy. Increased ploidy does not affect cardiac structure nor function in early adulthood, but correlates with a modest reduction in cardiac performance in aged mice. PIDDosome-imposed polyploidy control commences at postnatal day 7 (P7), reaching a plateau by P14. PIDDosome activation requires ANKRD26, targeting PIDD1 to mother centrioles. Opposite to prior observations in liver development, the PIDDosome limits CM polyploidization in a p53-independent manner but reliant on induction of p21/Cdkn1a, a notion supported by nuclear RNA sequencing and genetic deletion experiments. Our results provide new insights how proliferation of polyploid CMs is restricted during postnatal heart development.