UC San Diego

Congenital heart disease can result from defects in heart cell differentiation and morphogenesis during the early stages of cardiac development. Importantly, differentiation of the correct number of cardiomyocytes during these early stages ensures the proper function of the heart, as too few or too many cells can lead to a dysfunctional organ. While a few transcription factors have been shown to have roles in promoting myocardial differentiation, our knowledge of the important regulators of this process is incomplete. Here, we show that a bHLH transcription factor, Twist1a, functions to limit the production of myocardial cells in the early embryo. Reducing the function of twist1a in zebrafish embryos with an anti-twist1a morpholino (MO) results in expanded expression of cmlc2, a myocardial marker, suggesting a repressive role for Twist1a during myocardial differentiation. This role for Twist1a contrasts with that of Hand2, a bHLH transcription factor that is known to promote myocardial differentiation. We show that reducing the function of twist1a in hand2 hypomorphic mutants results in expanded cmlc2 expression. However, hand2 null mutants injected with the twist1a MO have no apparent increase in the expression of cmlc2. The idea that the function of Twist1a in limiting myocardial differentiation is dependent upon the presence of Hand2 supports our conclusion that the two transcription factors interact genetically during this process. Together, our findings suggest that the relative doses of Twist1a and Hand2 play an important role in setting the scale for the amount of myocardial differentiation in the zebrafish embryo