Histone Deacetylase 3 Regulates Smooth Muscle Differentiation in Neural Crest Cells and Development of the Cardiac Outflow Tract

Rationale: The development of the cardiac outflow tract (OFT) and great vessels is a complex process that involves coordinated regulation of multiple progenitor cell populations. Among these populations, neural crest cells make important contributions to OFT formation and aortic arch remodeling. Although numerous signaling pathways, including Notch, have been implicated in this process, the role of epigenetics in OFT development remains largely unexplored. Objective: Because histone deacetylases (Hdacs) play important roles in the epigenetic regulation of mammalian development, we have investigated the function of Hdac3, a class I Hdac, during cardiac neural crest development in mouse. Methods and Results: Using 2 neural crest drivers, Wnt1-Cre and Pax3(Cre), we show that loss of Hdac3 in neural crest results in perinatal lethality and cardiovascular abnormalities, including interrupted aortic arch type B, aortic arch hypoplasia, double-outlet right ventricle, and ventricular septal defect. Affected embryos are deficient in aortic arch artery smooth muscle during midgestation, despite intact neural crest cell migration and preserved development of other cardiac and truncal neural crest derivatives. The Hdac3-dependent block in smooth muscle differentiation is cell autonomous and is associated with downregulation of the Notch ligand Jagged1, a key driver of smooth muscle differentiation in the aortic arch arteries. Conclusions: These results indicate that Hdac3 plays a critical and specific regulatory role in the neural crest-derived smooth muscle lineage and in formation of the OFT. (Circ Res. 2011; 109: 1240-1249.)