The MEK-ERK signaling pathway promotes maintenance of cardiac chamber identity

Abstract

Ventricular and atrial cardiac chambers have unique structural and contractile characteristics that underlie their distinct functions. Intriguingly, the maintenance of chamber-specific features requires active reinforcement, even in differentiated cardiomyocytes. Prior studies in zebrafish have shown that sustained FGF signaling acts upstream of nkx2.5 to maintain ventricular identity, but the rest of this maintenance pathway remains unclear. Here, we show that MEK1/2-ERK1/2 signaling acts downstream of FGF and upstream of nkx2.5 to promote ventricular maintenance. Inhibition of MEK signaling, like inhibition of FGF signaling, results in ectopic atrial gene expression and reduced ventricular gene expression in ventricular cardiomyocytes. FGF and MEK signaling both influence ventricular maintenance over a similar timeframe, when phosphorylated ERK (pERK) is present in the myocardium. However, the role of FGF-MEK activity seems to be context-dependent: some ventricular regions are more sensitive than others to inhibition of FGF-MEK signaling. Additionally, in the atrium, although endogenous pERK does not induce ventricular traits, heightened MEK signaling can provoke ectopic ventricular gene expression. Together, our data reveal chamber-specific roles of MEK-ERK signaling in the maintenance of ventricular and atrial identities. SUMMARY STATEMENTThe MEK-ERK signaling pathway plays distinct roles in the maintenance of ventricular and atrial cardiomyocyte identities.