Dysregulated endocardial TGFβ signaling and mesenchymal transformation result in heart outflow tract septation failure

Dev Biol. 2016 Jan 1;409(1):272-276. doi: 10.1016/j.ydbio.2015.09.021. Epub 2015 Oct 29.


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.

Keywords: Common arterial trunk; Double outlet right ventricle; Endocardial–mesenchymal transformation; Persistent truncus arteriosus; Retinoic acid; TGFbeta.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Endocardium / embryology
  • Endocardium / metabolism
  • Endocardium / pathology*
  • Heart Failure / embryology
  • Heart Failure / metabolism
  • Heart Failure / pathology*
  • Heart Septal Defects / embryology
  • Heart Septal Defects / metabolism
  • Heart Septal Defects / pathology*
  • Mesoderm / embryology
  • Mesoderm / pathology*
  • Mice
  • Mutation / genetics
  • Organ Specificity
  • Phenotype
  • Receptors, Retinoic Acid / metabolism
  • Signal Transduction*
  • Transforming Growth Factor beta / metabolism*


  • Receptors, Retinoic Acid
  • Transforming Growth Factor beta