title: Tbx1 coordinates addition of posterior second heart field progenitor cells to the arterial and venous poles of the heart.
abstract: BACKGROUND
  Cardiac progenitor cells from the second heart field (SHF) contribute to rapid growth of the embryonic heart, giving rise to right ventricular and outflow tract (OFT) myocardium at the arterial pole of the heart, and atrial myocardium at the venous pole. Recent clonal analysis and cell-tracing experiments indicate that a common progenitor pool in the posterior region of the SHF gives rise to both OFT and atrial myocytes. The mechanisms regulating deployment of this progenitor pool remain unknown.
  
  
  OBJECTIVE
  To evaluate the role of TBX1, the major gene implicated in congenital heart defects in 22q11.2 deletion syndrome patients, in posterior SHF development.
  
  
  RESULTS
  Using transcriptome analysis, genetic tracing, and fluorescent dye-labeling experiments, we show that Tbx1-dependent OFT myocardium originates in Hox-expressing cells in the posterior SHF. In Tbx1 null embryos, OFT progenitor cells fail to segregate from this progenitor cell pool, leading to failure to expand the dorsal pericardial wall and altered positioning of the cardiac poles. Unexpectedly, addition of SHF cells to the venous pole of the heart is also impaired, resulting in abnormal development of the dorsal mesenchymal protrusion, and partially penetrant atrioventricular septal defects, including ostium primum defects.
  
  
  CONCLUSIONS
  Tbx1 is required for inflow as well as OFT morphogenesis by regulating the segregation and deployment of progenitor cells in the posterior SHF. Our results provide new insights into the pathogenesis of congenital heart defects and 22q11.2 deletion syndrome phenotypes.
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: M Sameer
authors.initials: MS
authors.lastname: Rana
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Magali
authors.initials: M
authors.lastname: Théveniau-Ruissy
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Christopher
authors.initials: C
authors.lastname: De Bono
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Karim
authors.initials: K
authors.lastname: Mesbah
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Alexandre
authors.initials: A
authors.lastname: Francou
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Mayyasa
authors.initials: M
authors.lastname: Rammah
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Jorge N
authors.initials: JN
authors.lastname: Domínguez
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Marine
authors.initials: M
authors.lastname: Roux
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Brigitte
authors.initials: B
authors.lastname: Laforest
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Robert H
authors.initials: RH
authors.lastname: Anderson
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Timothy
authors.initials: T
authors.lastname: Mohun
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Stephane
authors.initials: S
authors.lastname: Zaffran
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.).
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
authors.affiliation: From the Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.S.R., V.M.C.); CNRS, IBDM UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K.) and Inserm, GMGF UMR S910, Faculté de Médecine de la Timone (M.R., B.L., S.Z.), Aix Marseille Université, IBDM, CNRS UMR 7288 (M.T.-R., C.D.B., K.M., A.F., M.R., R.G.K) and GMGF Inserm URM S910 (M.R., B.L., S.Z.), Marseille, France; Department of Experimental Biology, University of Jaén, Jaén, Spain (J.N.D.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (R.H.A.); and MRC National Institute for Medical Research, Mill Hill, London, United Kingdom (T.M.). Robert.Kelly@univ-amu.fr.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kelly
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D004062:DiGeorge Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D006321:Heart / Q000196:embryology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse
keywords: DiGeorge syndrome; Tbx1 protein, mouse; heart defects, congenital