Abstract 2169: Jagged1/Notch Signaling in the Second Heart Field is Required for Proper Outflow Tract, Aortic Arch Artery, and Semilunar Valve Development
Mutations in the Notch pathway, including JAGGED1, a ligand in this signaling cascade, have been intimately linked to the formation of congenital heart disease. For example, JAGGED1 mutations are known to be causative in Alagille syndrome, while NOTCH1 mutations are implicated in bicuspid aortic valve disease. However, the exact role of Notch signaling during cardiogenesis remains poorly understood as well as how the myocardium, cardiac neural crest, and endocardium coordinately act to appropriately form the outflow tract. Here, we show that murine Jagged1 mediated Notch signaling is essential for proper cardiac outflow tract development. Deletion of Jagged1 or pan-inhibition of Notch signaling in the second heart field results in outflow tract anomalies, such as persistent truncus arteriousus and double outlet right ventricle, and aortic arch artery patterning defects. In addition, evaluation of these late stage embryos reveals structural defects of the semilunar valves and functional insufficiency. Thus, myocardial Notch inhibition can affect mature valve function. Jagged1/Notch signaling initiates a cascade of events in mid-gestation involving Fgf8, Bmp4, and downstream effectors that we implicate in this phenotype. In conclusion, our data suggest a model in which Jagged1/Notch signaling in second heart field helps coordinate the action of various cell fields in the formation of the outflow tract and semilunar valves, including migrating neural crest and endothelial-mesenchymal transition in the outflow tract endocardial cushions. Given that congenital heart disease affects nearly 1 in 100 live births and bicuspid aortic valve disease affects up to 2% of the adult population, a more detailed understanding of Jagged1/Notch signaling during cardiogenesis may provide a foundation upon which to build novel diagnostics and therapeutics for the management of these diseases.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).