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Article
Bicuspid aortic valve formation: Nos3 mutation leads to abnormal lineage patterning of neural crest cells and the second heart field
DMM Disease Models and Mechanisms
  • Joshua C. Peterson, Leids Universitair Medisch Centrum
  • Mary Chughtai, Leids Universitair Medisch Centrum
  • Lambertus J. Wisse, Leids Universitair Medisch Centrum
  • Adriana C. Gittenberger-De Groot, Leids Universitair Medisch Centrum
  • Qingping Feng, Schulich School of Medicine & Dentistry
  • Marie J.T.H. Goumans, Leids Universitair Medisch Centrum
  • J. Conny VanMunsteren, Leids Universitair Medisch Centrum
  • Monique R.M. Jongbloed, Leids Universitair Medisch Centrum
  • Marco C. DeRuiter, Leids Universitair Medisch Centrum
Document Type
Article
Publication Date
10-1-2018
URL with Digital Object Identifier
10.1242/dmm.034637
Abstract

The bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, belongs to the most prevalent congenital heart diseases in the world, occurring in 0.5-2% of the general population. We aimed to understand how changes in early cellular contributions result in BAV formation and impact cardiovascular outflow tract development. Detailed 3D reconstructions, immunohistochemistry and morphometrics determined that, during valvulogenesis, the non-coronary leaflet separates from the parietal outflow tract cushion instead of originating from an intercalated cushion. Nos3−/− mice develop a BAV without a raphe as a result of incomplete separation of the parietal outflow tract cushion into the right and non-coronary leaflet. Genetic lineage tracing of endothelial, second heart field and neural crest cells revealed altered deposition of neural crest cells and second heart field cells within the parietal outflow tract cushion of Nos3−/− embryos. The abnormal cell lineage distributions also affected the positioning of the aortic and pulmonary valves at the orifice level. The results demonstrate that the development of the right and non-coronary leaflets are closely related. A small deviation in the distribution of neural crest and second heart field populations affects normal valve formation and results in the predominant right-non-type BAV in Nos3−/− mice.

Citation Information
Joshua C. Peterson, Mary Chughtai, Lambertus J. Wisse, Adriana C. Gittenberger-De Groot, et al.. "Bicuspid aortic valve formation: Nos3 mutation leads to abnormal lineage patterning of neural crest cells and the second heart field" DMM Disease Models and Mechanisms Vol. 11 Iss. 10 (2018)
Available at: http://works.bepress.com/qingping-feng/9/