UC San Diego

The vertebrate heart is comprised of two types of chambers, ventricles and atria, which exhibit unique structural and contractile properties. Effective cardiac function depends upon the distinct morphological, physiological, and molecular characteristics of ventricular and atrial cardiomyocytes. Intriguingly, despite the early specification of ventricular and atrial lineages, chamber-specific features need to be actively reinforced even after myocardial differentiation is underway. By combining genetic and embryological approaches, work in zebrafish has revealed multiple players with potent influences on chamber fate specification and commitment. Notably, our prior studies in zebrafish have shown that sustained FGF signaling acts upstream of nkx2.5 to maintain ventricular chamber identity: upon inhibition of FGF signaling or loss of nkx2.5 function, ventricular cardiomyocytes extinguish expression of the ventricular gene vmhc and initiate ectopic expression of the atrial gene amhc. However, the rest of the pathway acting downstream of FGF signaling in this context remains largely unknown. Here, we show that MEK1/2-ERK1/2 signaling plays an important part in promoting ventricular identity maintenance. Pharmacological inhibition of MEK signaling results in ectopic amhc expression as well as reduced vmhc expression in ventricular cardiomyocytes. Epistasis analysis suggests that MEK signaling influences ventricular identity maintenance downstream of FGF signaling and upstream of nkx2.5 function. We find that FGF signaling and MEK signaling both influence ventricular identity maintenance over a similar timeframe, and we can detect phosphorylated ERK (pERK) in the myocardium during these stages. Intriguingly, the role of FGF-MEK activity seems to be context-dependent: some regions of the ventricle are more sensitive than others to inhibition of the FGF-MEK pathway. On the other hand, in the atrium, although endogenous levels of MEK-ERK signaling activity are not sufficient to induce ventricular traits in atrial cardiomyocytes, heightened MEK1 activity can provoke ectopic expression of vmhc. Together, our data indicate distinct functions of MEK-ERK signaling in the maintenance of ventricular and atrial identities.