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Development. 2018 Mar 6;145(5). pii: dev157206. doi: 10.1242/dev.157206.

Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration.

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Department of Developmental Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
Pediatric Institute for Heart Regeneration and Therapeutics (I-HRT), Richard King Mellon Foundation Institute for Pediatric Research and Division of Cardiology, Children's Hospital of Pittsburgh of UPMC and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA.
McGowan Institute of Regenerative Medicine, Pittsburgh, PA 15219, USA.
Department of Developmental Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA


Zebrafish regenerate cardiac tissue through proliferation of pre-existing cardiomyocytes and neovascularization. Secreted growth factors such as FGFs, IGF, PDGFs and Neuregulin play essential roles in stimulating cardiomyocyte proliferation. These factors activate the Ras/MAPK pathway, which is tightly controlled by the feedback attenuator Dual specificity phosphatase 6 (Dusp6), an ERK phosphatase. Here, we show that suppressing Dusp6 function enhances cardiac regeneration. Inactivation of Dusp6 by small molecules or by gene inactivation increased cardiomyocyte proliferation, coronary angiogenesis, and reduced fibrosis after ventricular resection. Inhibition of Erbb or PDGF receptor signaling suppressed cardiac regeneration in wild-type zebrafish, but had a milder effect on regeneration in dusp6 mutants. Moreover, in rat primary cardiomyocytes, NRG1-stimulated proliferation can be enhanced upon chemical inhibition of Dusp6 with BCI. Our results suggest that Dusp6 attenuates Ras/MAPK signaling during regeneration and that suppressing Dusp6 can enhance cardiac repair.


Cardiac repair; Cardiomyocyte proliferation; Dual specificity phosphatase 6; Heart regeneration; Ras/MAPK signaling; Zebrafish

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