Disruption of Tnnt2-Cre+/Isl1+ progenitors in the outflow wall via Notch-Jag signaling or SHF deficiency results in leaflet dysplasia and bicuspid aortic valves without raphe in mice.
This study identifies a novel source of valve interstitial cells and provides a new mechanism for the causation of bicuspid aortic valves without raphe, challenging the dogma that heart valves are formed principally by EndMT.
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.
Eley et al. (Fri,) conducted a other in Bicuspid aortic valve. Genetic disruption of Notch-Jag signaling or SHF addition vs. Control littermates was evaluated on Development of bicuspid aortic valve without raphe or leaflet dysplasia. Disruption of Tnnt2-Cre+/Isl1+ progenitors in the outflow wall via Notch-Jag signaling or SHF deficiency results in leaflet dysplasia and bicuspid aortic valves without raphe in mice.