A novel source of arterial valve cells linked to bicuspid aortic valve without raphe in mice

Elife. 2018 Jun 29;7:e34110. doi: 10.7554/eLife.34110.


Abnormalities of the arterial valve leaflets, predominantly bicuspid aortic valve, are the commonest congenital malformations. Although many studies have investigated the development of the arterial valves, it has been assumed that, as with the atrioventricular valves, endocardial to mesenchymal transition (EndMT) is the predominant mechanism. We show that arterial is distinctly different from atrioventricular valve formation. Whilst the four septal valve leaflets are dominated by NCC and EndMT-derived cells, the intercalated leaflets differentiate directly from Tnnt2-Cre+/Isl1+ progenitors in the outflow wall, via a Notch-Jag dependent mechanism. Further, when this novel group of progenitors are disrupted, development of the intercalated leaflets is disrupted, resulting in leaflet dysplasia and bicuspid valves without raphe, most commonly affecting the aortic valve. This study thus overturns the dogma that heart valves are formed principally by EndMT, identifies a new source of valve interstitial cells, and provides a novel mechanism for causation of bicuspid aortic valves without raphe.

Keywords: arterial valve; bicuspid aortic valve; developmental biology; human; mouse; progenitor; second heart field.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Valve / abnormalities*
  • Aortic Valve / metabolism
  • Aortic Valve / pathology
  • Bicuspid Aortic Valve Disease
  • Biomarkers / metabolism
  • Cell Differentiation
  • Cell Lineage / genetics
  • Cell Tracking / methods
  • Embryo, Mammalian
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Gene Expression
  • Heart Valve Diseases / genetics
  • Heart Valve Diseases / metabolism
  • Heart Valve Diseases / pathology*
  • Humans
  • Integrases / genetics
  • Integrases / metabolism
  • Jagged-1 Protein / genetics*
  • Jagged-1 Protein / metabolism
  • LIM-Homeodomain Proteins / genetics
  • LIM-Homeodomain Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology*
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Stem Cells / metabolism
  • Stem Cells / pathology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Troponin T / genetics
  • Troponin T / metabolism


  • Biomarkers
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • LIM-Homeodomain Proteins
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Tnnt2 protein, mouse
  • Transcription Factors
  • Troponin T
  • insulin gene enhancer binding protein Isl-1
  • Cre recombinase
  • Integrases