Histone deacetylase 1 controls cardiomyocyte proliferation during embryonic heart development and cardiac regeneration in zebrafish.

Anja Bühler,Mohankrishna Dalvoy,Gilbert Weidinger,Steffen Just,Bernhard Kühn,Rhett A Kovall,Franz Oswald,Bernd M Gahr,Alexander Pott,Alena Boos,Deung-Dae Park,Alberto Bertozzi,Wolfgang Rottbauer,Frank L Conlon

doi:10.1371/journal.pgen.1009890

Abstract

In contrast to mammals, the zebrafish maintains its cardiomyocyte proliferation capacity throughout adulthood. However, neither the molecular mechanisms that orchestrate the proliferation of cardiomyocytes during developmental heart growth nor in the context of regeneration in the adult are sufficiently defined yet. We identified in a forward genetic N-ethyl-N-nitrosourea (ENU) mutagenesis screen the recessive, embryonic-lethal zebrafish mutant baldrian (bal), which shows severely impaired developmental heart growth due to diminished cardiomyocyte proliferation. By positional cloning, we identified a missense mutation in the zebrafish histone deacetylase 1 (hdac1) gene leading to severe protein instability and the loss of Hdac1 function in vivo. Hdac1 inhibition significantly reduces cardiomyocyte proliferation, indicating a role of Hdac1 during developmental heart growth in zebrafish. To evaluate whether developmental and regenerative Hdac1-associated mechanisms of cardiomyocyte proliferation are conserved, we analyzed regenerative cardiomyocyte proliferation after Hdac1 inhibition at the wound border zone in cryoinjured adult zebrafish hearts and we found that Hdac1 is also essential to orchestrate regenerative cardiomyocyte proliferation in the adult vertebrate heart. In summary, our findings suggest an important and conserved role of Histone deacetylase 1 (Hdac1) in developmental and adult regenerative cardiomyocyte proliferation in the vertebrate heart.

Highlights

The adult human heart is unable to sufficiently regenerate after myocardial infarction
In an ENU-mutagenesis screen, we identified the zebrafish mutant baldrian, which shows reduced embryonic cardiomyocyte proliferation
As genetic cause of the observed phenotype, we identified a missense mutation in the hdac1 gene

Summary

Introduction

The adult human heart is unable to sufficiently regenerate after myocardial infarction. Low level cardiomyocyte proliferation and turnover was described in adult mammalian hearts, which is insufficient to regenerate the heart after acute or chronic damage [1,2]. The control of cardiomyocyte proliferation in the developing heart depends on both, cell cycle activating and inhibiting pathways, and both mechanisms seem to play a fundamental role in the induction of postnatal cardiomyocyte proliferation. Tbox transcription factor 20 (Tbx20) was found to play a crucial role in the control of cardiomyocyte proliferation in the developing heart in zebrafish and mice [3,4,5], and in the adult heart since transgenic induction of Tbx in adult mice significantly augments cardiomyocyte proliferation after myocardial injury by inducing proliferative and repressing cell cycle inhibitory pathways [6]

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