When it first starts to develop, the heart is a simple tube. Reporting in the journal Nature Communications, researchers have now described how it forms itself into a its characteristic S-shape and how the ventricles and atria finally develop. Their findings will help scientists to better understand the development of congenital heart diseases.
By conducting experiments with zebrafish, researchers have identified the mechanisms by which the heart takes on its fully developed form. Their study reports how the heart first develops into a tube-like form through the continuous flow of heart precursor cells.
"We then turned to the question of how the linear tube loops round into the characteristic S-shape, which ultimately goes on to form the ventricle and the atrium of the zebrafish heart," says one of the study's two lead authors. "For this process to occur, the second-generation heart cells need to integrate into the linear heart and identify their correct place." Author explains that this involves relocations of the cells. "They change their neighbors and find new cells to share the cell boundaries with," says the author.
As they report, this process is controlled by a signalling pathway - a chain of chemical reactions that cause the cells to react to external signals - known as the PCP signalling pathway triggered by two non-canonical Wnt ligands, Wnt5b and Wnt11. PCP stands for 'planar cell polarity'. Two components are especially important to this pathway: the molecules Fzd7a and Vangl2. "When we deactivated the genes for these molecules in zebrafish, the heart was unable to develop properly," says the author. "Clearly, the cells were unable to locate their future neighbors."
The PCP signalling pathway influences not just individual cells but also the tissue as a whole. "If the signalling pathway is disrupted in some way, the tissue tension changes," says the author. Without the correct tension, the looping process cannot take place and the formation of the heart is impaired. As the researchers discovered in further experiments, the change in tissue tension is due to the fact that the defective PCP signalling pathway alters the cytoskeleton of the heart muscle cells. The cytoskeleton consists of the proteins actin and myosin and enables muscle cells and therefore an entire muscle to contract.
"Normally we observe that the cytoskeleton in the heart cells doesn't look the same everywhere, but exhibits polarity," explains the author. "The surface of the cells differ from their base." If the PCP signalling pathway is disrupted, this polarity is lost. As a result, the tube-shaped heart cannot take on its new form properly. "The outflow tract, in particular, is unable to develop correctly," author explains. Most congenital heart diseases are due to problems in this part of the organ.
Authors carried out their experiments on zebrafish, because these animals have the important advantage that the heart develops very quickly and starts to beat just 24 hours after fertilization. "But we're confident that our findings can be transferred to mammals, including humans," says the senior uthor. "The PCP signalling pathway is highly conserved in evolutionary terms and the genes involved in it have already been identified in humans and associated with congenital heart disease."
Next, the team are planning to carry out studies with heart tissue from patients with the congenital heart diseases tetralogy of Fallot and DORV (double outlet right ventricle). Through their experiments, the researchers aim to identify exactly to what extent a disrupted PCP signalling pathway is implicated in the development of these diseases.
Cell and tissue polarity required for heart development!
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