Strong evidence – Essential regulatory gene for the formation of heart valves discovered

In the embryonic zebrafish heart, the endocardium that is forming cardiac valve leaflets is divided into two subpopulations (here, cyan and yellow). | Photo: Federica Fontana
Source: Federica Fontana
In the embryonic zebrafish heart, the endocardium that is forming cardiac valve leaflets is divided into two subpopulations (here, cyan and yellow). Yellow cells are in contact with blood flow and express Notch, while Vegfr3/Flt4 is active within the cyan cells that lack blood flow stimuli. Their antagonistic activities shape the cardiac valves.

By studying zebrafish embryos, the animal physiologist Prof. Salim Seyfried and his team have identified a new blood flow-regulated gene (Vegfr3/Flt4) in the inner wall lining of the heart, which plays an important role in the formation of cardiac valves. Their results published in the journal „Cell Reports“ are crucial to understand heart development and the basis of congenital cardiac malformations. Salim Seyfried is affiliated with the Institute of Biochemistry and Biology at the University of Potsdam and with the Hannover Medical School.

During embryonic development, the heart is the first organ that becomes functional and generates blood flow throughout the body. The special thing about its morphogenesis is the interconnection with the biomechanical forces due to blood flow. These forces have a big impact in particular on the cells that line the interior of the heart. From these cells, cardiac valves are formed to ensure an unidirectional flow of blood.
Zebrafish eggs can easily be manipulated and are therefore a widely used model system in biomedical research. Taking advantage of the zebrafish embryo, the researchers around Salim Seyfried combined in vivo imaging and gene expression profiling - the measurement of the activity of thousands of genes at once - to visualize the conversion of genetic information into proteins (gene expression) under conditions with and without blood flow, respectively. They observed higher Vegfr3/Flt4 gene expression in endocardial cells that lost contact to blood flow after they migrated into the area between the endocardium and the myocardium.
By studying zebrafish embryos that are defective for the Vegfr3/Flt4 gene, the team found that Vegfr3/Flt4 is essential for the proper formation of cardiac valves. Federica Fontana, first author of the paper now published, explains: „In particular, our work suggests that valve endocardial cells in the area between the endocardium and the myocardium loose expression of another gene (Notch), due to the lack of mechanical stimuli, and this triggers gene expression of Vegfr3/Flt4. In turn, Vegfr3/Flt4 suppresses the Notch-gene in these cells.” These activities represent a fine-tuned gene regulatory mechanism, essential to shape cardiac valve leaflets by inducing unique differences in the fates of endocardial cells.

Link to Publication: Federica Fontana, Timm Haack, Maria Reichenbach, Petra Knaus, Michel Puceat, Salim Abdelilah-Seyfried, 2020, Antagonistic Activities of Vegfr3/Flt4 and Notch1b Fine-tune Mechanosensitive Signaling during Zebrafish Cardiac Valvulogenesis, Cell Reports 32, 107883, https://doi.org/10.1016/j.celrep.2020.107883

Image: In the embryonic zebrafish heart, the endocardium that is forming cardiac valve leaflets is divided into two subpopulations (here, cyan and yellow). Yellow cells are in contact with blood flow and express Notch, while Vegfr3/Flt4 is active within the cyan cells that lack blood flow stimuli. Their antagonistic activities shape the cardiac valves. Image Credit: Federica Fontana

Contact:
Prof. Dr. Salim Seyfried, Institute of Biochemistry and Biology, Tel.: +49 331 977-5540, salim.seyfrieduni-potsdamde
Federica Fontana, Institute of Biochemistry and Biology, Tel.: +49 331 977-5539, fontanatuni-potsdamde

Media Information 03-08-2020 / Nr. 075