Europe PMC

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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 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.

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    Funding 


    Funders who supported this work.

    Austrian Science Fund FWF (3)

    • Grant ID: P36658

    • Grant ID: I6662

    • Grant ID: M3115B

    California Tobacco Related Disease Research Program

      Deutsche Forschungsgemeinschaft (2)

      • Grant ID: CRC/TRR353

      • Grant ID: INST 95/1650-1

      Deutsche Forschungsgemeinschaft (German Research Foundation) (2)

      • Grant ID: INST 95/1650-1

      • Grant ID: CRC/TRR353

      Österreichischen Akademie der Wissenschaften

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