Three Proteins in Cellular Antennae Linked to Congenital Heart Defects

Three proteins—TAK1, TAB2, and PKA-Cα—form a previously unknown signaling center inside the primary cilium, a microscopic cellular “antenna” critical for embryonic heart formation, researchers at the University of Copenhagen have reported.

How the cilium directs organ development

The primary cilium extends from most human cells and functions as a sensory hub, interpreting extracellular signals to regulate cell division, migration, and death. Within this structure, the newly identified trio of proteins acts as molecular instructions guiding stem cells to differentiate into heart muscle cells during early development.

“These proteins act as molecular instructions that tell stem cells when and how to develop into heart muscle cells. However, genetic alterations can disrupt this communication, causing ‘antenna defects,’ which may lead to congenital heart defects,” explains Søren Tvorup Christensen, Professor of cell biology at the Department of Biology.

Genetic data and cross-species experiments converge

To trace the mechanism, the team integrated genetic data from several thousand individuals diagnosed with congenital heart disease with experimental models including zebrafish, human cells, and mouse stem cells.

They first scanned patient genomes for rare mutations occurring more frequently among affected individuals than in healthy controls—flagging variants potentially tied to disease. Using genetic engineering, they introduced those same mutations into zebrafish embryos and observed resulting developmental abnormalities and impaired cardiac function.

Parallel laboratory studies across multiple human cell types mapped the molecular consequences of pathway disruption, ultimately converging on the primary cilium as the site where the signaling defect originates.

“We investigate the mechanism from many different angles and using many different methods, all of which support what we observe in patients. Therefore, we are reasonably confident that this mechanism also exists in humans,” says Lars Allan Larsen, Professor at the Department of Cellular and Molecular Medicine and an expert in congenital heart disease.

A unifying explanation for syndromic defects

The mutations were found predominantly in patients with syndromic congenital heart disease—conditions in which a single underlying genetic syndrome produces heart defects alongside structural or functional abnormalities in other organs.

Zebrafish experiments and tissue-level analyses of cilia confirmed the same signaling system operates during the development of brain, kidney, and skeletal tissues. When the cilium’s signaling fails, disruptions commonly appear across multiple organ systems.

“When the ciliary mechanism fails, it typically affects the development of several other organs as well. This may explain why some patients with congenital heart disease also have defects and related conditions affecting the brain, kidneys, and skeleton. The mechanism provides a unifying explanation for diseases that we have previously struggled to understand,” says Christensen.

Potential implications for diagnosis and therapy

About two of every 100 babies worldwide are born with congenital heart disease, yet the biological origins remain incompletely understood. This discovery adds a concrete molecular pathway to the explanatory framework—particularly for cases linked to dysfunctional primary cilia.

“Many rare genetic diseases are caused by changes in genes that affect ciliary function, yet the underlying mechanisms have remained poorly understood. This new knowledge may eventually make it easier to identify patients early and develop targeted treatments,” says Larsen.

“We have discovered a new communication system on the exterior of the cell that is crucial for the proper formation of the heart during embryonic development. This finding changes our understanding of how congenital heart defects arise. You could say that we have identified an important cog in a highly complex machine,” Larsen adds.

Reference: “TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development” by Canan Doganli, Oskar Kaaber Thomsen, Daniel A. Baird, Yeasmeen Ali, Menachem V. K. Sarusie, Enrique Audain, Line Jeanett Jessen, Pauline Munck Truelsen, Johanne Bay Mogensen, Maria Schrøder Holm, Kateřina Apolínová, Lorenzo Buttò, Maria Diamanti, Jindřiška Leischner Fialová, Emma M. Wade, Stephen P. Robertson, Lotte Bang Pedersen, Laurent Argiro, Fabienne Lescroart, Marc-Phillip Hitz, Søren Tvorup Christensen and Lars Allan Larsen, 4 August 2026, PLOS Biology.
DOI: 10.1371/journal.pbio.3003902