Cardiac diseases are a leading cause of death worldwide as mammals cannot regenerate their heart effectively.  One reason for this lack of regenerative capacity is insufficient cardiomyocyte (CM) renewal, by which CMs dedifferentiate, proliferate and redifferentiate to replace lost CMs. 

Erbb2, a receptor tyrosine kinase, has been implicated in CM regeneration.  Overexpression of constitutively active ERBB2 in mouse CMs promotes both their dedifferentiation and proliferation after myocardial infarction.  In zebrafish, a regenerative model, overexpression of the Erbb2 ligand Nrg1 enhances dedifferentiation and proliferation.  Nevertheless, it is not clear whether erbb2 is essential for CM dedifferentiation and proliferation during zebrafish heart regeneration.

Here, both an inducible dominant negative (DN) erbb2 line and a floxed erbb2 line are being established in zebrafish, as erbb2 mutants are not viable.  Expression of the DN-erbb2 is temporally controlled by heatshock and tamoxifen treatment and CMs expressing the DN-erbb2 can be identified by mScarlet expression.  This strategy should indicate whether mScarlet-expressing CMs can dedifferentiate and proliferate.  In the floxed erbb2 line, recombination will produce a truncated protein at the tyrosine kinase domain.  Therefore recombination should abrogate Erbb2-mediated signal transduction.  While these tools are established and validated, CM dedifferentiation and proliferation are being assessed after treatment with an Erbb inhibitor.  Preliminary data suggest that inhibiting Erbb signalling during regeneration leads to a decrease in a CM dedifferentiation marker.

On the whole, Nrg/Erbb2 signalling has been implicated in CM dedifferentiation and proliferation from gain-of-function experiments but more investigation is needed to delineate its role in zebrafish heart regeneration, which could open the door to new therapeutic strategies for patients.