title: Cardiac outflow morphogenesis depends on effects of retinoic acid signaling on multiple cell lineages.
abstract: BACKGROUND
  Retinoic acid (RA), the bioactive derivative of vitamin A, is essential for vertebrate heart development. Both excess and reduced RA signaling lead to cardiovascular malformations affecting the outflow tract (OFT). To address the cellular mechanisms underlying the effects of RA signaling during OFT morphogenesis, we used transient maternal RA supplementation to rescue the early lethality resulting from inactivation of the murine retinaldehyde dehydrogenase 2 (Raldh2) gene.
  
  
  RESULTS
  By embryonic day 13.5, all rescued Raldh2(-/-) hearts exhibit severe, reproducible OFT septation defects, although wild-type and Raldh2(+/-) littermates have normal hearts. Cardiac neural crest cells (cNCC) were present in OFT cushions of Raldh2(-/-) mutant embryos but ectopically located in the periphery of the endocardial cushions, rather than immediately underlying the endocardium. Excess mesenchyme was generated by Raldh2(-/-) mutant endocardium, which displaced cNCC derivatives from their subendocardial, medial position.
  
  
  CONCLUSIONS
  RA signaling affects not only cNCC numbers but also their position relative to endocardial mesenchyme during the septation process. Our study shows that inappropriate coordination between the different cell types of the OFT perturbs its morphogenesis and leads to a severe congenital heart defect, persistent truncus arteriosus.
authors.affiliation: Aix-Marseille University, GMGF, UMR_S910, Faculté de Médecine, Marseille, France.|INSERM U910, Faculté de Médecine, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: El Robrini
authors.affiliation: Aix-Marseille University, GMGF, UMR_S910, Faculté de Médecine, Marseille, France.|INSERM U910, Faculté de Médecine, Marseille, France.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Etchevers
authors.affiliation: Aix-Marseille University, GMGF, UMR_S910, Faculté de Médecine, Marseille, France.|INSERM U910, Faculté de Médecine, Marseille, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Ryckebüsch
authors.affiliation: Aix-Marseille University, GMGF, UMR_S910, Faculté de Médecine, Marseille, France.|INSERM U910, Faculté de Médecine, Marseille, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Faure
authors.affiliation: Aix-Marseille University, GMGF, UMR_S910, Faculté de Médecine, Marseille, France.|INSERM U910, Faculté de Médecine, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Eudes
authors.affiliation: CNRS UMR 7104, INSERM U964, IGBMC, University of Strasbourg, Illkirch, France.
authors.forename: Karen
authors.initials: K
authors.lastname: Niederreither
authors.affiliation: Aix-Marseille University, GMGF, UMR_S910, Faculté de Médecine, Marseille, France.|INSERM U910, Faculté de Médecine, Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Zaffran
authors.affiliation: Aix-Marseille University, GMGF, UMR_S910, Faculté de Médecine, Marseille, France.|INSERM U910, Faculté de Médecine, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bertrand
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019070:Cell Lineage / Q000502:physiology*; D006321:Heart / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse
keywords: congenital heart defect; endocardium; mouse; myocardium; neural crest; persistent truncus arteriosus; retinoic acid