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Proteolysis regulates cardiomyocyte maturation and tissue integration

Author

Listed:
  • Ryuichi Fukuda

    (Max Planck Institute for Heart and Lung Research)

  • Felix Gunawan

    (Max Planck Institute for Heart and Lung Research)

  • Arica Beisaw

    (Max Planck Institute for Heart and Lung Research)

  • Vanesa Jimenez-Amilburu

    (Max Planck Institute for Heart and Lung Research)

  • Hans-Martin Maischein

    (Max Planck Institute for Heart and Lung Research)

  • Sawa Kostin

    (Max Planck Institute for Heart and Lung Research)

  • Koichi Kawakami

    (National Institute of Genetics)

  • Didier Y. R. Stainier

    (Max Planck Institute for Heart and Lung Research)

Abstract

Tissue integrity is critical for organ formation and function. During heart development, cardiomyocytes differentiate and integrate to form a coherent tissue that contracts synchronously. However, the molecular mechanisms regulating cardiac tissue integrity are poorly understood. Here we show that proteolysis, via the E3 ubiquitin ligase ASB2, regulates cardiomyocyte maturation and tissue integrity. Cardiomyocytes in asb2b zebrafish mutants fail to terminally differentiate, resulting in reduced cardiac contractility and output. Mosaic analyses reveal a cell-autonomous requirement for Asb2b in cardiomyocytes for their integration as asb2b mutant cardiomyocytes are unable to meld into wild-type myocardial tissue. In vitro and in vivo data indicate that ASB2 negatively regulates TCF3, a bHLH transcription factor. TCF3 must be degraded for cardiomyocyte maturation, as TCF3 gain-of-function causes a number of phenotypes associated with cardiomyocyte dedifferentiation. Overall, our results show that proteolysis has an important role in cardiomyocyte maturation and the formation of a coherent myocardial tissue.

Suggested Citation

  • Ryuichi Fukuda & Felix Gunawan & Arica Beisaw & Vanesa Jimenez-Amilburu & Hans-Martin Maischein & Sawa Kostin & Koichi Kawakami & Didier Y. R. Stainier, 2017. "Proteolysis regulates cardiomyocyte maturation and tissue integration," Nature Communications, Nature, vol. 8(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14495
    DOI: 10.1038/ncomms14495
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    Cited by:

    1. Marga Albu & Eileen Affolter & Alessandra Gentile & Yanli Xu & Khrievono Kikhi & Sarah Howard & Carsten Kuenne & Rashmi Priya & Felix Gunawan & Didier Y. R. Stainier, 2024. "Distinct mechanisms regulate ventricular and atrial chamber wall formation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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