Cardiac outflow tract valve development and pathophysiology in zebrafish

• Applicant: Professor Dr. Salim Seyfried
• Subject Area: Developmental Biology ; Cardiology, Angiology ; Cell Biology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407481317

The formation of cardiac valves is a developmental process triggered by mechanical forces exerted by blood flow and involves interactions of endothelial cells with cardiomyocytes or vascular smooth muscle cells. The formation of the aortic valve is of particular biomedical interest because malformations that arise due to the fusion of two leaflets cause the bicuspid aortic valve (BAV) representing the most common congenital heart defect. Strikingly, BAV is linked to life-threatening defects of the descending aorta, including thoracic aorta dilations, aneuyrisms and aortic stenosis. Hence, there is a great biomedical need to identify the genetic causes and to elucidate the molecular and cellular consequences of particular gene variants associated with BAV. Genome-wide association studies (GWAS) and next generation sequencing approaches on patient-derived tissues have been instrumental in identifying large numbers of both high- and low-risk variants for BAV. Hence, there is an urgent need for suitable model organisms to validate and functionally characterize candidate gene variants for BAV. Developing such animal models also holds the promise of better understanding the aetiopathology of severe aortic defects linked to BAV. During the first funding period, we focussed on the formation of cardiac valves at the atrioventricular canal (AVC) of the zebrafish heart. This extension grant will build on that expertise and focus on the formation and pathophysiology of the outflow tract region of the zebrafish heart. In particular, we will address the molecular and cellular interactions between outflow tract endothelial cells and vascular smooth muscle cells during morphogenesis of the outflow tract arterial valve and its neighboring aorta. Despite morphological differences between zebrafish arterial valves and human aortic valves (the former being bicuspid), the molecular and cellular processes during valvulogenesis share large similarities between zebrafish, mouse and man. A detailed molecular and cellular characterization of arterial valvulogenesis is even more warranted because increasing evidence suggests that there are striking differences in the way arterial and atrioventricular valves form. This work will draw on a fruitful collaboration with clinical partners that have performed extensive GWAS and exome sequencing studies in BAV patient cohorts, resulting in the identification of several candidate genes including FBN2. In addition, components related to TGF-ß and nitric oxide signalling have been implicated in BAV. Here, we aim at a comprehensive view, at single cell resolution, on the roles of Fbn2, TGF-ß, and nitric oxide signalling during morphogenesis of the outflow tract arterial valve and aorta of zebrafish.

• DFG Programme: Research Grants