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Dis Model Mech. 2018 Oct 19;11(10). pii: dmm034637. doi: 10.1242/dmm.034637.

Bicuspid aortic valve formation: Nos3 mutation leads to abnormal lineage patterning of neural crest cells and the second heart field.

Author information

1
Dept. Anatomy and Embryology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
2
Dept. Cardiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
3
Dept. Physiology and Pharmacology, Schulich Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada.
4
Dept. Molecular Cell Biology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
5
Dept. Anatomy and Embryology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands m.c.deruiter@lumc.nl.

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.

KEYWORDS:

Bicuspid aortic valve; Development; Embryo; Lineage tracing; Nos3; Outflow tract

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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