Copenhagen team links primary-cilium TAK1 signal center to congenital heart defects

SciTechDaily reported that University of Copenhagen researchers identified a signaling mechanism in primary cilia that may help explain congenital heart defects and related multi-organ disease. About two of every 100 babies worldwide are born with congenital heart disease. The team found that three proteins, TAK1, TAB2, and PKA-Cα, form a signaling center inside the primary cilium, a microscopic antenna-like structure on most cells that helps cells decide whether to divide, move, or die. Professor Lars Allan Larsen said the communication system on the cell exterior is crucial for proper heart formation during embryonic development. Professor Søren Tvorup Christensen said the proteins act as molecular instructions telling stem cells when and how to become heart muscle cells, and that genetic alterations can disrupt that communication. Researchers combined genetic data from several thousand people with congenital heart defects with experiments in zebrafish, human cells, and mouse stem cells. Rare mutations that appeared more often in patients than healthy people caused developmental abnormalities and impaired heart function when reproduced in zebrafish. The mutations appeared in patients with syndromic congenital heart disease affecting other organs as well. Zebrafish work and cilia analyses indicated the same mechanism contributes to development of multiple organs, including brain, kidneys, and skeleton. The paper, on TAK1 at the primary cilium in non-canonical TGFB/BMP signaling, was published in PLOS Biology with DOI: 10.1371/journal.pbio.3003902.