title: Tbx5 is required for avian and Mammalian epicardial formation and coronary vasculogenesis.
abstract: BACKGROUND
  Holt-Oram syndrome is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. Overexpression of Tbx5 in the chick proepicardial organ impaired coronary blood vessel formation. However, the potential activity of Tbx5 in the epicardium itself, and the role of Tbx5 in mammalian coronary vasculogenesis, remains largely unknown.
  
  
  OBJECTIVE
  To evaluate the consequences of altered Tbx5 gene dosage during proepicardial organ and epicardial development in the embryonic chick and mouse.
  
  
  RESULTS
  Retroviral-mediated knockdown or upregulation of Tbx5 expression in the embryonic chick proepicardial organ and proepicardial-specific deletion of Tbx5 in the embryonic mouse (Tbx5(epi-/)) impaired normal proepicardial organ cell development, inhibited epicardial and coronary blood vessel formation, and altered developmental gene expression. The generation of epicardial-derived cells and their migration into the myocardium were impaired between embryonic day (E) 13.5 to 15.5 in mutant hearts because of delayed epicardial attachment to the myocardium and subepicardial accumulation of epicardial-derived cells. This caused defective coronary vasculogenesis associated with impaired vascular smooth muscle cell recruitment and reduced invasion of cardiac fibroblasts and endothelial cells into myocardium. In contrast to wild-type hearts that exhibited an elaborate ventricular vascular network, Tbx5(epi-/-) hearts displayed a marked decrease in vascular density that was associated with myocardial hypoxia as exemplified by hypoxia inducible factor-1α upregulation and increased binding of hypoxyprobe-1. Tbx5(epi-/-) mice with such myocardial hypoxia exhibited reduced exercise capacity when compared with wild-type mice.
  
  
  CONCLUSIONS
  Our findings support a conserved Tbx5 dose-dependent requirement for both proepicardial and epicardial progenitor cell development in chick and in mouse coronary vascular formation.
authors.affiliation: From the Center for Molecular Cardiology, Greenberg Division of Cardiology (N.Y.S.-G.D., G.B., B.P.T.K., C.T.B., C.J.H.) and Department of Physiology and Biophysics (O.E.), Weill Cornell Medical College, New York, NY; Department of Genetics, Harvard Medical School, Boston, MA (J.G.S., C.E.S.); and Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, PA (C.J.H.).
authors.forename: Nata Y S-G
authors.initials: NY
authors.lastname: Diman
authors.affiliation: From the Center for Molecular Cardiology, Greenberg Division of Cardiology (N.Y.S.-G.D., G.B., B.P.T.K., C.T.B., C.J.H.) and Department of Physiology and Biophysics (O.E.), Weill Cornell Medical College, New York, NY; Department of Genetics, Harvard Medical School, Boston, MA (J.G.S., C.E.S.); and Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, PA (C.J.H.).
authors.forename: Gabriel
authors.initials: G
authors.lastname: Brooks
authors.affiliation: From the Center for Molecular Cardiology, Greenberg Division of Cardiology (N.Y.S.-G.D., G.B., B.P.T.K., C.T.B., C.J.H.) and Department of Physiology and Biophysics (O.E.), Weill Cornell Medical College, New York, NY; Department of Genetics, Harvard Medical School, Boston, MA (J.G.S., C.E.S.); and Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, PA (C.J.H.).
authors.forename: Boudewijn P T
authors.initials: BP
authors.lastname: Kruithof
authors.affiliation: From the Center for Molecular Cardiology, Greenberg Division of Cardiology (N.Y.S.-G.D., G.B., B.P.T.K., C.T.B., C.J.H.) and Department of Physiology and Biophysics (O.E.), Weill Cornell Medical College, New York, NY; Department of Genetics, Harvard Medical School, Boston, MA (J.G.S., C.E.S.); and Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, PA (C.J.H.).
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: From the Center for Molecular Cardiology, Greenberg Division of Cardiology (N.Y.S.-G.D., G.B., B.P.T.K., C.T.B., C.J.H.) and Department of Physiology and Biophysics (O.E.), Weill Cornell Medical College, New York, NY; Department of Genetics, Harvard Medical School, Boston, MA (J.G.S., C.E.S.); and Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, PA (C.J.H.).
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: From the Center for Molecular Cardiology, Greenberg Division of Cardiology (N.Y.S.-G.D., G.B., B.P.T.K., C.T.B., C.J.H.) and Department of Physiology and Biophysics (O.E.), Weill Cornell Medical College, New York, NY; Department of Genetics, Harvard Medical School, Boston, MA (J.G.S., C.E.S.); and Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, PA (C.J.H.).
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.affiliation: From the Center for Molecular Cardiology, Greenberg Division of Cardiology (N.Y.S.-G.D., G.B., B.P.T.K., C.T.B., C.J.H.) and Department of Physiology and Biophysics (O.E.), Weill Cornell Medical College, New York, NY; Department of Genetics, Harvard Medical School, Boston, MA (J.G.S., C.E.S.); and Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, PA (C.J.H.). cathyha@pcom.edu craig.basson@novartis.com.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Basson
authors.affiliation: From the Center for Molecular Cardiology, Greenberg Division of Cardiology (N.Y.S.-G.D., G.B., B.P.T.K., C.T.B., C.J.H.) and Department of Physiology and Biophysics (O.E.), Weill Cornell Medical College, New York, NY; Department of Genetics, Harvard Medical School, Boston, MA (J.G.S., C.E.S.); and Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, PA (C.J.H.). cathyha@pcom.edu craig.basson@novartis.com.
authors.forename: Cathy J
authors.initials: CJ
authors.lastname: Hatcher
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002642:Chick Embryo; D003331:Coronary Vessels / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D038081:Organogenesis / Q000502:physiology*; D010496:Pericardium / Q000196:embryology* / Q000378:metabolism*; D013045:Species Specificity; D020825:T-Box Domain Proteins / Q000096:biosynthesis* / Q000172:deficiency
chemical_list: D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5
keywords: Tbx5; cell adhesion; cell migration; coronary vessels; epicardium; myocardium; transcription factors