Australian researchers have uncovered a crucial new mechanism that helps explain how the heart’s major blood vessels form during early development, and how disruptions to this process can lead to serious congenital heart defects.
The study, led by scientists from Adelaide University, reveals that a specific group of cells known as neural crest cells play a previously unrecognised role in controlling heart development by carefully regulating a key growth signal.
The findings, published in Nature Communications, shed new light on the origins of conditions such as Tetralogy of Fallot, one of the most common forms of congenital heart disease.
Congenital heart disease affects around one in every 100 infants worldwide. It happens when the heart’s outflow tract – the section that directs blood from the heart to the body and lungs – does not form correctly during early pregnancy.
The new research shows that neural crest cells act as molecular ‘traffic controllers’, ensuring that heart muscle precursor cells develop at the right time and place.
“Heart development is an incredibly precise process,” said study lead author Dr Sophie Wiszniak from Adelaide University’s Centre for Cancer Biology (CCB).
“Cells need to stay in a flexible, immature state long enough for the heart to grow properly and then switch on muscle development at exactly the right moment. What we’ve discovered is a new way this balance is controlled.”
At the centre of the discovery is a protein called NEDD4, which functions like a quality-control manager inside cells. NEDD4 keeps levels of another protein, DKK1, under tight control. DKK1 acts as a brake on a major developmental pathway known as Wnt signalling, which is essential for maintaining heart progenitor cells in an undifferentiated, growth-ready state.
The researchers found that neural crest cells are a key source of DKK1 near the developing heart. By adjusting how much DKK1 is present, these cells fine-tune Wnt signalling in neighbouring heart progenitor cells, allowing the heart’s outflow tract to lengthen and align correctly.
When NEDD4 does not function properly, DKK1 levels rise too high. This prematurely shuts down Wnt signalling, causing heart progenitor cells to differentiate into muscle too early. The result is a shortened, misaligned outflow tract – a hallmark of several serious congenital heart defects.
Using genetically engineered mouse models, the team showed that removing NEDD4 specifically from neural crest cells led to outflow tract defects resembling those seen in affected children.
Importantly, reducing DKK1 levels partially rescued normal heart development, confirming its central role in the process.
The study also provides compelling evidence linking this pathway to human disease.
The researchers identified a rare inherited variant in the NEDD4 gene in a child with Tetralogy of Fallot. Laboratory tests showed that this variant reduces NEDD4’s ability to control DKK1, while mice engineered to carry the same genetic mutation developed heart abnormalities similar to those seen in patients.
“This is a powerful example of how basic developmental biology can directly inform our understanding of human disease,” said senior author CCB researcher Professor Quenten Schwarz.
“By identifying the molecular pathway involved, we now have a clearer picture of how certain congenital heart defects arise.”
Beyond its clinical implications, the discovery challenges long-standing assumptions about neural crest cells, which were previously thought to play mostly structural roles in heart development.
“Our findings show that neural crest cells also act as signalling hubs,” Dr Wiszniak said. “They don’t just build parts of the heart – they help instruct other cells how to behave.”
The researchers hope this work will pave the way for improved genetic diagnosis of congenital heart disease and, in the longer term, contribute to strategies aimed at preventing or correcting these defects before birth.
‘Neural crest cell-derived DKK1 and NEDD4 modulate Wnt signalling in the second heart field to orchestrate outflow tract development’ is published in Nature Communications.
DOI: 10.1038/s41467-026-68459-4