Researchers from the group of Jeroen Bakkers, in collaboration with Leiden University and the Amsterdam UMC, provide a detailed description of cardiac looping during zebrafish embryonic development. They show that the gene tbx5 plays an important role in this process and is essential for correct formation of the heart. Furthermore, they demonstrate that the heart does not depend on surrounding tissues during heart looping. The results were published in eLife on 10 August and contribute to our knowledge about congenital heart defects.

Cardiac looping takes place during embryonic development. It transforms the straight embryonic heart tube into a S-shaped heart, which makes sure that the building blocks of the developing heart end up at the right place. Transposition of the Great Arteries (TGA) and double-outlet-right-ventricle (DORV) are congenital heart defects that arise when errors occur during cardiac looping, causing the great arteries to end up at the wrong place. To better understand these and other congenital heart defects, the group of Jeroen Bakkers together with researchers from Leiden University and the Amsterdam UMC studied cardiac looping in detail in zebrafish.

Twisting of the heart tube
In their new study, the researchers looked at the movements of all heart muscle cells, also called cardiomyocytes, over time in zebrafish embryos, creating a 4D map of the zebrafish embryonic heart. The coordinated movements of all these cardiomyocytes together result in twisting of the heart tube. Once the team determined how cardiomyocytes behave in a healthy heart, they looked at the heart of zebrafish with mutations in the gene tbx5.

Independent heart
The study shows that tbx5 is essential for the twisting and looping movements of cardiomyocytes, which is in turn essential for correct formation of the heart. This mechanism does not require any help from surrounding tissue; the heart only depends on itself for its correct formation. Mutations in tbx5 impair cardiac looping and cause congenital heart defects in zebrafish. Patients with mutations in this gene also show congenital heart defects.

Congenital heart defects
The results of this study provide insights into the process of cardiac looping and the way in which it ensures correct formation of the heart. Additionally, they contribute to our knowledge about congenital heart defects such as TGA and DORV. The study is related to a nationwide research project into congenital heart defects funded by De Hartstichting and Stichting Hartekind.

Photo: Jeroen Bakkers is professor Moleculaire Cardiogenetica at UMC Utrecht and group leader at the Hubrecht Institute.