Heart defects are the most common congenital defect, yet scientists still struggle to understand why they occur. A new study from the Max Delbruck Center for Molecular Medicine investigates a signaling pathway in the developing heart that works similarly in both zebrafish and humans.
To learn more about what causes congenital heart defects, scientists often study embryonic heart development: looking at how the heart develops to understand what goes wrong and identifying what mechanisms are necessary for healthy development. Additionally, scientists often conduct experiments with zebrafish, which have unique regenerative abilities.
In the newest study, scientists looked at the progression of heart development in zebrafish as it forms into a linear tube-like form, then its characteristic “S-shape,” and then into atria and ventricle chambers.
"For this process to occur, the second-generation heart cells need to integrate into the linear heart and identify their correct place," explained lead author Anne Margarete Merks. "They change their neighbors and find new cells to share the cell boundaries with."
Merks says that this process requires a constant influx of heart precursor cells, the cells that eventually development into full-fledged heart muscle cells, called cardiomyocytes. Researchers found that this process is largely regulated by the PCP (planar cell polarity) signaling pathway, particularly molecules Fzd7a and Vangl2. When these two molecules were genetically deactivated, the zebrafish heart could not develop correctly. In Merks’ words: “clearly, the cells were unable to locate their future neighbors.”
"The PCP signaling 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,” explained team leader Dr. Daniela Panakova. This evolutionary conservation is vital for the results of their studies to translate into meaningful conclusions for human congenital heart disease.
Researchers found that when the PCP signaling pathways malfunctions, whole tissues are affected. Specifically, changing tissue tension inhibits formation of the heart. Tissue tension change is caused by PCP alteration of the cytoskeleton in cardiomyocytes. The cytoskeleton contains two key proteins for contracting muscles: actin and myosin.
Normally, the cytoskeleton exhibits polarity, but malfunction of the PCP signaling pathway destroys polarity, leading to the inhibition of proper heart development. Merks says that the loss polarity affects the “outflow tract” in particular, a developing organ most often associated with congenital heart disease.
Going forward, scientists from the present study plan to apply their current findings to studies with human heart tissue donated by patients with congenital heart disease. Potentially, identifying changes in the PCP signaling pathway could one day help scientists intervene early or prevent congenital heart defects all together.
The present study was published in the journal Nature Communications.