Proteolysis regulates cardiomyocyte maturation and tissue integration

Ryuichi Fukuda (), Felix Gunawan, Arica Beisaw, Vanesa Jimenez-Amilburu, Hans-Martin Maischein, Sawa Kostin, Koichi Kawakami and Didier Y. R. Stainier ()
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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

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14495

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