title: Histone deacetylase 3 regulates smooth muscle differentiation in neural crest cells and development of the cardiac outflow tract.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Cell and Developmental Biology, the Cardiovascular Institute, Pereleman School of Medicine at the University of Pennsylvania, Philadelphia, 19104, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Singh
authors.forename: Chinmay M
authors.initials: CM
authors.lastname: Trivedi
authors.forename: MinMin
authors.initials: M
authors.lastname: Lu
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Mullican
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D000313:Adrenal Medulla / Q000196:embryology; D000818:Animals; D001013:Aorta, Thoracic / Q000002:abnormalities; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D002465:Cell Movement; D004310:Double Outlet Right Ventricle / Q000196:embryology / Q000201:enzymology / Q000235:genetics; D005260:Female; D005318:Fetal Heart / Q000201:enzymology* / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D006345:Heart Septal Defects, Ventricular / Q000196:embryology / Q000201:enzymology / Q000235:genetics; D006352:Heart Ventricles / Q000196:embryology / Q000201:enzymology; D006655:Histone Deacetylases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000473:pathology*; D009432:Neural Crest / Q000473:pathology*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology; D013950:Thymus Gland / Q000002:abnormalities*; D051155:Wnt1 Protein / Q000502:physiology; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D051880:Receptors, Notch; D051155:Wnt1 Protein; D000099186:Histone Deacetylase 3; C495246:Wnt1 protein, mouse; C068686:Pax3 protein, mouse