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Open AccessFeature PaperArticle

Human ARF Specifically Inhibits Epimorphic Regeneration in the Zebrafish Heart

1
Department of Surgery, Division of Plastic Surgery, Program in Craniofacial Biology, University of California, San Francisco, CA 94143, USA
2
Department of Surgery and Orofacial Sciences, Program in Craniofacial Biology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA
3
Department of Surgery, Division of Plastic Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
4
Department of Surgery and Orofacial Sciences, Division of Plastic Surgery, Program in Craniofacial Biology, University of California, San Francisco, CA 94143, USA
5
Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA
*
Author to whom correspondence should be addressed.
Genes 2020, 11(6), 666; https://doi.org/10.3390/genes11060666
Received: 29 May 2020 / Revised: 13 June 2020 / Accepted: 16 June 2020 / Published: 18 June 2020
(This article belongs to the Special Issue Mechanisms Governing ARF Levels)
The Alternative Reading Frame (ARF) protein is a tumor suppressor encoded by the Cyclin Dependent Kinase Inhibitor 2A gene in mammals but not lower regenerative vertebrates, and has been previously implicated as a context-sensitive suppressor of regeneration in murine skeletal muscle and humanized ARF-expressing zebrafish fins. This study extends our investigation of the role of ARF in the regeneration of other solid tissues, including the zebrafish heart and the mammalian digit. Heart regeneration after cryoinjury was used to mimic massive myocardial infarction. ARF gene expression was upregulated during the cardiac regenerative process and slowed the rate of morphological recovery. ARF specifically impacts cardiomyocytes, neovascularization, and the endothelial-mesenchymal transition, while not affecting epicardial proliferation. This suggests that in the context of regeneration, ARF is specifically expressed in cells undergoing dedifferentiation. To investigate ARF as a suppressor of epimorphic regeneration in mammalian systems, we also tested whether the absence of ARF was permissive for murine digit regeneration, but found that ARF absence alone was insufficient to significantly alter digit restoration. These findings provide additional evidence that ARF suppresses epimorphic regeneration, but suggests that modulation of ARF alone is insufficient to permit regeneration. View Full-Text
Keywords: Alternative Reading Frame (ARF); cardiac regeneration; epimorphic regeneration Alternative Reading Frame (ARF); cardiac regeneration; epimorphic regeneration
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MDPI and ACS Style

Lee, S.; Hesse, R.; Tamaki, S.; Garland, C.; Pomerantz, J.H. Human ARF Specifically Inhibits Epimorphic Regeneration in the Zebrafish Heart. Genes 2020, 11, 666.

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