The heart is the first functional organ that develops in vertebrate embryos. In humans, it starts to beat four weeks into the pregnancy. Unfortunately, congenital heart disease is one of the most common developmental abnormalities and the leading cause of birth defect-related deaths. These heart defects often involve malformations of cardiac valves, which are required to regulate the pressure and flow of blood in the cardiac chambers.
Now, researchers have identified a key regulator gene for the formation of cardiac valves - a process crucial to normal embryonic heart development. These results are published in the journal Cell Reports.
The team has identified the so-called HAND2 gene as a key regulator that triggers the formation of cardiac valves in mouse embryos, a process that is crucial for normal heart development. Previous research using mouse models lacking HAND2 had shown that this gene regulates outflow tract and right ventricle development.
The researchers thus set out to identify the set of genes that are controlled by HAND2 in developing mouse hearts. In doing so, they identified a previously unknown heart defect in mouse embryos lacking HAND2. The mutant hearts lack the cardiac cushions, which would normally develop into cardiac valves. Normally, the cells contributing to these cushions undergo complex cellular rearrangements from endothelial to mesenchymal (EMT) as they detach from the lining of the heart wall and migrate into the cushions to "fill them up" in the atrioventricular canal (AVC). As this mechanism is crucial for heart development, the researchers investigated how HAND2 controls this fundamental event during cardiac valve development.
The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost from Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues.
In humans, defects in valve formation underlie different congenital heart malformations but the molecular mechanisms controlling heart valve development are not well understood. By studying mouse embryos, the research group has now identified the network of genes directly controlled by HAND2 that regulates cardiac valve formation.
The discovery of the HAND2 controlled gene network is of general relevance as mutations in HAND2 have recently been linked to heart valve malformations in human patients. «Not only does this discovery advance our molecular knowledge of cardiac valve development, but it may also help to provide genetic diagnosis for patients that suffer from congenital heart malformations, says first author.
Key regulatory gene in cardiac valve formation discovered!
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