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

Development (Cambridge, England) (2018-02-16)
Maria A Missinato, Manush Saydmohammed, Daniel A Zuppo, Krithika S Rao, Graham W Opie, Bernhard Kühn, Michael Tsang
ZUSAMMENFASSUNG

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.

MATERIALIEN
Produktnummer
Marke
Produktbeschreibung

Sigma-Aldrich
Monoklonales Anti-α-Aktinin (Sarkomer) in Maus hergestellte Antikörper, clone EA-53, ascites fluid
Sigma-Aldrich
Anti-Phospho-Histon H3 (Ser10)-Antikörper, Mitosemarker, Upstate®, from rabbit
Sigma-Aldrich
Monoklonales Anti-PCNA (Proliferating Cell Nuclear Antigen) in Maus hergestellte Antikörper, clone PC 10, ascites fluid
Sigma-Aldrich
Monoklonale Anti-MAP-Kinase, aktiviert (Diphosphorylierter ERK-1&2) in Maus hergestellte Antikörper, clone MAPK-YT, ascites fluid
Sigma-Aldrich
Tyrphostin AG 1478, ≥98%
Sigma-Aldrich
Monoclonal Anti-DUSP6 antibody produced in mouse, clone 3G2, purified immunoglobulin, buffered aqueous solution