A calcineurin–Hoxb13 axis regulates growth mode of mammalian cardiomyocytes

Ngoc Uyen Nhi Nguyen, Diana C. Canseco, Feng Xiao, Yuji Nakada, Shujuan Li, Nicholas T. Lam, Shalini A. Muralidhar, Jainy J. Savla, Joseph A. Hill, Victor Le, Kareem A. Zidan, Hamed W. El-Feky, Zhaoning Wang, Mahmoud Salama Ahmed, Maimon E. Hubbi, Ivan Menendez-Montes, Jesung Moon, Shah R. Ali, Victoria Le, Elisa Villalobos, Magid S. Mohamed, Waleed M. Elhelaly, Suwannee Thet, Chukwuemeka George Anene-Nzelu, Wilson Lek Wen Tan, Roger S. Foo, Xun Meng, Mohammed Kanchwala, Chao Xing, Jagoree Roy, Martha S. Cyert, Beverly A. Rothermel and Hesham A. Sadek ()
Additional contact information
Ngoc Uyen Nhi Nguyen: The University of Texas Southwestern Medical Center
Diana C. Canseco: The University of Texas Southwestern Medical Center
Feng Xiao: The University of Texas Southwestern Medical Center
Yuji Nakada: The University of Texas Southwestern Medical Center
Shujuan Li: The University of Texas Southwestern Medical Center
Nicholas T. Lam: The University of Texas Southwestern Medical Center
Shalini A. Muralidhar: The University of Texas Southwestern Medical Center
Jainy J. Savla: The University of Texas Southwestern Medical Center
Joseph A. Hill: The University of Texas Southwestern Medical Center
Victor Le: The University of Texas Southwestern Medical Center
Kareem A. Zidan: The University of Texas Southwestern Medical Center
Hamed W. El-Feky: The University of Texas Southwestern Medical Center
Zhaoning Wang: The University of Texas Southwestern Medical Center
Mahmoud Salama Ahmed: The University of Texas Southwestern Medical Center
Maimon E. Hubbi: The University of Texas Southwestern Medical Center
Ivan Menendez-Montes: The University of Texas Southwestern Medical Center
Jesung Moon: The University of Texas Southwestern Medical Center
Shah R. Ali: The University of Texas Southwestern Medical Center
Victoria Le: The University of Texas Southwestern Medical Center
Elisa Villalobos: The University of Texas Southwestern Medical Center
Magid S. Mohamed: The University of Texas Southwestern Medical Center
Waleed M. Elhelaly: The University of Texas Southwestern Medical Center
Suwannee Thet: The University of Texas Southwestern Medical Center
Chukwuemeka George Anene-Nzelu: National University of Singapore
Wilson Lek Wen Tan: National University of Singapore
Roger S. Foo: National University of Singapore
Xun Meng: Northwest University
Mohammed Kanchwala: The University of Texas Southwestern Medical Center
Chao Xing: The University of Texas Southwestern Medical Center
Jagoree Roy: Stanford University
Martha S. Cyert: Stanford University
Beverly A. Rothermel: The University of Texas Southwestern Medical Center
Hesham A. Sadek: The University of Texas Southwestern Medical Center

Nature, 2020, vol. 582, issue 7811, 271-276

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2228-6

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