Transcriptional pathways in heart development

Abstract

The second heart field (SHF) is a cardiac progenitor population that resides in the splanchnic and pharyngeal mesoderm and is progressively added to the linear heart tube at the time of cardiac looping to gives rise to the outflow tract (OFT), right ventricle (RV), ventricular septum, and portions of the left ventricle. Although much has been learned regarding the contributions of the SHF to the developing heart, several crucial questions remain regarding the molecular pathways that control SHF development. The LIM‐homeodomain transcription factor ISL1 is required for SHF development and sits at or near the top of a transcriptional cascade for the development of this progenitor population. Likewise, the MADS domain transcription factor MEF2C is required for RV and OFT development. We identified Mef2c as a direct transcriptional target of ISL1 via a novel SHF‐specific enhancer, establishing a direct link between these two essential factors.We have recently identified a novel mesoderm‐specific enhancer from the Isl1 gene, which we are analyzing to define early steps in SHF specification. This enhancer directs expression to the SHF from early cardiac crescent stage through pharyngeal mesoderm development. We are defining the pathways upstream of this novel Isl1 enhancer, and we are continuing our analyses of the Mef2c SHF enhancer with the goal of defining the mechanism through which ISL1 results in sustained activation in the RV and OFT after Isl1 expression itself is extinguished. These data and a SHF transcriptional network involving ISL1, GATA4, Nkx2‐5, MEF2C and other factors will be presented.