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bioRxiv · 10.1101/2024.08.27.609375

The PIDDosome controls cardiomyocyte polyploidization during postnatal heart development

Leone, M.·Eichin, F.·Kinz, N.·Obwegs, D.·Sladky, V. C.·Rizzotto, D.·Manzl, C.·Moos, K.·Savko, C.·Jacotot, E. D.·Sussman, M.·Boerries, M.·Villunger, A.
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Abstract

The adult mammalian heart is characterized by post-mitotic polyploid cardiomyocytes (CMs). Understanding how CMs regulate cell cycle exit and ploidy 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 PIDDosome-loss causes a cell-autonomous increase in nuclear and cellular CM ploidy. Remarkably, increased ploidy does not affect cardiac structure nor function. PIDDosome-imposed ploidy restriction commences at postnatal day 7 (P7), reaching a plateau on 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 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.

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Leone, M., Eichin, F., Kinz, N., Obwegs, D., Sladky, V. C., Rizzotto, D., Manzl, C., Moos, K., Savko, C., Jacotot, E. D., Sussman, M., Boerries, M., Villunger, A.. 2024-08-28. The PIDDosome controls cardiomyocyte polyploidization during postnatal heart development. https://doi.org/10.1101/2024.08.27.609375

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