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A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes.

Ngoc Uyen Nhi NguyenDiana C CansecoFeng XiaoYuji NakadaShujuan LiNicholas T LamShalini A MuralidharJainy J SavlaJoseph A HillVictor LeKareem A ZidanHamed W El-FekyZhaoning WangMahmoud Salama AhmedMaimon E HubbiIvan Menendez-MontesJesung MoonShah R AliVictoria LeElisa VillalobosMagid S MohamedWaleed M ElhelalySuwannee ThetChukwuemeka George Anene-NzeluWilson Lek Wen TanRoger S FooXun MengMohammed KanchwalaChao XingJagoree RoyMartha S CyertBeverly A RothermelHesham A Sadek
Published in: Nature (2020)
A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of cardiomyocyte proliferation and reactivate the cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes.
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