title: Dysregulated endocardial TGFβ signaling and mesenchymal transformation result in heart outflow tract septation failure.
abstract: Heart outflow tract septation in mouse embryos carrying mutations in retinoic acid receptor genes fails with complete penetrance. In this mutant background, ectopic TGFβ signaling in the distal outflow tract is responsible for septation failure, but it was uncertain what tissue was responsive to ectopic TGFβ and why this response interfered with septation. By combining RAR gene mutation with tissue-specific Cre drivers and a conditional type II TGFβ receptor (Tgfbr2) allele, we determined that ectopic activation of TGFβ signaling in the endocardium is responsible for septation defects. Ectopic TGFβ signaling results in ectopic mesenchymal transformation of the endocardium and thereby in improperly constituted distal OFT cushions. Our analysis highlights the interactions between myocardium, endocardium, and neural crest cells in outflow tract morphogenesis, and demonstrates the requirement for proper TGFβ signaling in outflow tract cushion organization and septation.
authors.affiliation: Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Mancheong
authors.initials: M
authors.lastname: Ma
authors.affiliation: Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Shen
authors.affiliation: Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Kristine D
authors.initials: KD
authors.lastname: Estrada
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: S Ram
authors.initials: SR
authors.lastname: Kumar
authors.affiliation: Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: sucov@usc.edu.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Sucov
mesh_terms: D000818:Animals; D004699:Endocardium / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D006333:Heart Failure / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D006343:Heart Septal Defects / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000196:embryology / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009928:Organ Specificity; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018168:Receptors, Retinoic Acid; D016212:Transforming Growth Factor beta
keywords: Common arterial trunk; Double outlet right ventricle; Endocardial–mesenchymal transformation; Persistent truncus arteriosus; Retinoic acid; TGFbeta