ETS1 and HLHS: Implications for the Role of the Endocardium

We have identified the ETS1 gene as the cause of congenital heart defects, including an unprecedented high frequency of HLHS, in the chromosomal disorder Jacobsen syndrome. Studies in Ciona intestinalis demonstrated a critical role for ETS1 in heart cell fate determination and cell migration, suggesting that the impairment of one or both processes can underlie the pathogenesis of HLHS. Our studies determined that ETS1 is expressed in the cardiac neural crest and endocardium in the developing murine heart, implicating one or both lineages in the development of HLHS. Studies in Drosophila and Xenopus demonstrated a critical role for ETS1 in regulating cardiac cell fate determination, and results in Xenopus provided further evidence for the role of the endocardium in the evolution of the "hypoplastic" HLHS LV. Paradoxically, these studies suggest that the loss of ETS1 may cause a cell fate switch resulting in the loss of endocardial cells and a relative abundance of cardiac myocytes. These studies implicate an "HLHS transcriptional network" of genes conserved across species that are essential for early heart development. Finally, the evidence suggests that in a subset of HLHS patients, the HLHS LV cardiac myocytes are, intrinsically, developmentally and functionally normal, which has important implications for potential future therapies.