A newly discovered communication system within the microscopic "antennae" of cells may help explain how some congenital heart defects develop. This system, found in a structure called the primary cilium, could also play a role in the development of other organs, such as the brain, kidneys, and skeleton. Congenital heart disease affects about two out of every 100 newborns worldwide, making it one of the most common types of birth defects. Researchers at the University of Copenhagen have identified a previously unknown mechanism that may be a key part of the explanation. The newly identified mechanism operates within the primary cilium, a tiny, antenna-like structure found on the surface of most cells in the body. These cilia help cells detect and interpret chemical signals from their environment, which can influence critical decisions such as whether a cell divides, moves, or dies. The researchers discovered that three proteins—TAK1, TAB2, and PKA-Cα—work together inside the cilium as a signaling hub. Their activity appears to be essential for the normal development of the heart. These proteins act as molecular instructions that guide stem cells to transform into heart muscle cells. However, genetic mutations can disrupt this communication, leading to "antenna defects" that may cause congenital heart defects. Congenital heart disease refers to structural abnormalities of the heart that develop during embryonic life. Each year, about 2.3 to 2.5 million newborns worldwide are affected by this condition, and an estimated 16 million people live with congenital heart disease globally (data from 2023). The current study focuses on syndromic congenital heart disease, where heart defects are part of a broader genetic syndrome that can also affect other organs. To investigate the system, the researchers combined genetic data from people with congenital heart defects with experiments using zebrafish, human cells, and mouse stem cells. They analyzed genetic data from thousands of patients, looking for rare mutations and comparing how often these genetic changes appeared in affected individuals versus healthy ones. Variants that were more common in patients were considered more likely to be linked to the condition. The team then tested the impact of these genetic changes in laboratory settings. Using genetic engineering, scientists recreated the same mutations in zebrafish and observed how they affected heart development. The results showed that changes in these genes can interfere with normal heart formation and reduce heart function in zebrafish. In laboratory experiments, the researchers also studied various cell types, allowing them to examine the signaling system in detail and understand the consequences of disrupting its molecular communication pathways. The findings from patient genetics and experimental models point to the primary cilium as a key player in the process that may contribute to congenital heart defects. The primary cilium helps cells sense their surroundings and respond to signals like hormones and growth factors. These signals guide cells in making decisions about division, movement, and function. The cilia are especially important during embryonic development, helping to coordinate the formation of organs like the heart, brain, and skeleton. The researchers also found that the mechanism may influence the development of organs beyond the heart. The rare mutations studied were found in individuals with syndromic congenital heart disease, where heart defects are part of a broader genetic syndrome that can also affect other parts of the body. Experiments in zebrafish, along with detailed studies of cilia in other tissues, suggest that the same cellular mechanism may contribute to the development of multiple organs. When this ciliary mechanism fails, it can affect several other organs, explaining why some patients with congenital heart disease also have defects in the brain, kidneys, and skeleton. This discovery offers a unified explanation for a range of previously poorly understood diseases. The study has been published in the scientific journal PLOS Biology.