Researchers at the University of Copenhagen have identified a previously unknown cellular mechanism that may help explain how some congenital heart defects develop.

“We have discovered a new communication system on the outside of cells that is important for the proper formation of the heart during fetal development. This discovery changes our understanding of why some congenital heart defects occur. We can say that we have identified a key cog in a very complex machine,” says Lars Alan Larsen, an expert on congenital heart disease and professor at the Department of Cellular and Molecular Medicine.

How primary cilia guide heart development

The newly identified mechanism operates within primary cilia—microscopic, antenna-like structures that extend from the surface of most cells in the body.

Primary cilia help cells sense and interpret chemical signals from their surroundings. These signals can influence important cell decisions, including whether a cell divides, migrates, changes its metabolism, develops into a specific cell type, or dies.

The researchers discovered that three proteins—TAK1, TAB2, and PKA-Cα—work together as a signaling hub inside these cellular antennas. Their activity appears to be important for the normal formation of the heart.

“These proteins act as molecular instructions that tell stem cells when and how to develop into heart muscle cells. However, genetic mutations can disrupt this communication, causing ‘antenna defects’ and leading to congenital heart defects,” explains Soren Tvorp Christensen, professor of cell biology in the Department of Biology.

What is congenital heart disease?

Congenital heart disease refers to structural abnormalities of the heart that occur during fetal development.

Each year, approximately 2.3 to 2.5 million newborns worldwide are affected by congenital heart disease. An estimated 16 million people live with congenital heart disease, according to 2023 data. Together, these figures make congenital heart disease one of the most common congenital diseases worldwide.

Some congenital heart defects occur as part of a broader genetic syndrome and may also cause abnormalities elsewhere in the body. These cases are known as syndromic congenital heart disease. When a child has congenital heart disease without other complications, the condition is classified as nonsyndromic congenital heart disease. The current research focuses on syndromic heart defects.

Source: World Heart Federation and Danish Heart Foundation

Researchers tested the mechanism using zebrafish and stem cells

To investigate how this signaling system works, the researchers combined genetic data from people with congenital heart disease with experiments involving zebrafish, human cells, and mouse stem cells.

They began by analyzing genetic information from thousands of patients with congenital heart defects. The team searched for rare mutations and compared how often specific genetic changes appeared in patients and healthy people. Variants that occurred more frequently among patients were considered more likely to contribute to disease symptoms.

The researchers then tested the effects of these genetic changes in laboratory models.

Using genetic engineering, they recreated the same mutations in zebrafish and examined how the changes affected heart formation. The results showed that mutations in these genes can interfere with normal heart development and reduce heart function in zebrafish.

The team also studied several cell types in laboratory experiments. These tests allowed the researchers to examine the signaling system in greater detail and determine what happens when its molecular communication pathways are disrupted.

Together, the patient genetic data and laboratory findings pointed to primary cilia as an important part of the process that may contribute to congenital heart disease.

“We are studying this mechanism from different angles and using different methods, all of which confirm what we observed in patients. We are therefore confident that this mechanism also exists in humans,” says Lars Alan Larsen.

What are primary cilia?

Primary cilia are tiny, antenna-like structures that protrude from the surface of most cells. Their main role is to help cells sense information from their surroundings.

They can detect signaling molecules, including hormones and growth factors, and convert those signals into instructions that guide cell behavior. These messages can tell cells when to divide, change their metabolism, generate new tissue, migrate, or die.

Primary cilia are present on almost all cell types and are especially important during embryonic development. They help regulate the formation of organs such as the heart, brain, and skeleton. Because of this widespread role, problems with ciliary function can affect multiple organs at the same time.

Source: Lars Alan Larsen and Soren Tvorup Christensen

Cellular mechanism may affect more than the heart

The researchers also found evidence that this mechanism may influence the development of organs beyond the heart.

The rare mutations examined in the study were identified in people with syndromic congenital heart defects. In these cases, the heart defect is part of a broader genetic syndrome that can affect other parts of the body.

Experiments in zebrafish, along with detailed studies of cilia in other tissues, suggested that the same cellular machinery may contribute to the development of several organs.

“When the ciliary machinery malfunctions, it usually affects the development of several other organs. This may explain why some patients with congenital heart disease have defects and associated diseases that affect the brain, kidneys, and skeleton. This mechanism provides a unifying explanation for a disease that has so far been difficult to understand,” says Soren Tvorup Christensen.

Problems involving primary cilia are already known to be associated with several rare genetic diseases. The researchers believe their discovery may improve scientists’ understanding of a wider range of conditions linked to ciliary function.

“Many rare genetic diseases are caused by changes in genes that affect ciliary body function, but the underlying mechanisms are still poorly understood. This new knowledge could ultimately make it easier to identify patients earlier and develop targeted treatments,” says Lars Alan Larsen.

What the study could mean for congenital heart disease research

The study examined how specific signaling pathways within primary cilia influence heart development during embryonic development. The researchers combined genetic analysis of patients with congenital heart disease with experiments involving zebrafish, mouse stem cells, and cell models.

The findings suggest that this signaling pathway contributes to cardiomyocyte development and the proper formation of the heart during fetal life.

Researchers have not yet clearly established how the mechanism works in humans because the evidence comes primarily from genetic associations and experimental models. However, taken together, the findings provide strong evidence that the same process may be involved in human heart development.

The study has been published in the scientific journal PLOS Biology.

University of Copenhagen researchers who contributed to the study include Søren Tvorup Christensen, Lars Allan Larsen, Canan Doganli, Oskar Kaaber Thomsen, Daniel A. Baird, Yasmeen Ali, Menachem VK Salusie, Line Jeanett Jessen, Pauline Munck Truelsen, Johanne Bay Mogensen, Maria Schrøder Holm, Lorenzo Buttò, Maria Diamanti, Zinjiszka Reischner Fialova, and Lotte van Pedersen.