TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development
9 affiliations
- 1Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
- 2Department of Biology, University of Copenhagen, Copenhagen, Denmark
- 3Department of Medical Genetics, Carl von Ossietzky University, Oldenburg, Germany
- 4Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
- 5ZeClinics SL, Badalona, Spain
- 6Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, New Zealand
- 7Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- 8Aix Marseille Université, INSERM, MMG U1251, Marseille, France
- 9College of Health Sciences, VinUniversity, Hanoi, Vietnam
Abstract
Pathogenic variants in the genes encoding the non-canonical TGFB signaling components TAK1 (MAP3K7 ) , TAB2 and PKA-Cα (PRKACA) cause rare multisystem disorders, which may include congenital heart disease (CHD). To investigate the role of TAK1 signaling in CHD, we performed genetic analysis of CHD patients and discovered an increased burden of rare TAB2 and TAK1 variants in patients with extracardiac abnormalities. To address the mechanism of TAK1 in heart development, we performed experiments in cell and animal models. Zebrafish tak1 and tab2 mutants presented with cardiac and extracardiac developmental defects, and tak1 mutant hearts showed downregulation of genes encoding core cardiac transcription factors, sarcomeric proteins and extracellular matrix proteins. In vitro experiments indicated that TAK1 via TAB2 and PKA-Cα is activated at the primary cilium during cardiomyogenesis; activation at this site is enhanced by TGFB/BMP ligands. Inactivation of TAK1 inhibited ciliary signaling and cardiomyocyte differentiation, and patient-derived TAK1 variants reduced its ciliary localization. In conclusion, our data establish a pivotal role for TAK1 and its upstream regulators at the primary cilium in heart development and syndromic CHD.
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BibTeX
@article{doganlı2026tak1,
title = {{TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development}},
author = {Canan Doğanlı and Oskar Kaaber Thomsen and Daniel A. Baird and Yeasmeen Ali and Menachem Viktor Sarusie and Enrique Audain and Line Jeanett Jessen and Pauline Munck Truelsen and Johanne Bay Mogensen and Maria Schrøder Holm and Kateřina Apolínová and Lorenzo Buttò and Maria Diamanti and Jindřiška Leischner Fialová and Emma M. Wade and Stephen P. Robertson and Lotte Bang Pedersen and Laurent Argiro and Fabienne Lescroart and Marc‐Phillip Hitz and Søren T. Christensen and Lars Allan Larsen},
journal = {PLoS Biology},
year = {2026},
month = aug,
doi = {10.1371/journal.pbio.3003902},
url = {https://doi.org/10.1371/journal.pbio.3003902},
note = {CC BY},
}
RIS
TY - JOUR
TI - TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development
AU - Canan Doğanlı
AU - Oskar Kaaber Thomsen
AU - Daniel A. Baird
AU - Yeasmeen Ali
AU - Menachem Viktor Sarusie
AU - Enrique Audain
AU - Line Jeanett Jessen
AU - Pauline Munck Truelsen
AU - Johanne Bay Mogensen
AU - Maria Schrøder Holm
AU - Kateřina Apolínová
AU - Lorenzo Buttò
AU - Maria Diamanti
AU - Jindřiška Leischner Fialová
AU - Emma M. Wade
AU - Stephen P. Robertson
AU - Lotte Bang Pedersen
AU - Laurent Argiro
AU - Fabienne Lescroart
AU - Marc‐Phillip Hitz
AU - Søren T. Christensen
AU - Lars Allan Larsen
PY - 2026
DA - 2026/08/04
JO - PLoS Biology
DO - 10.1371/journal.pbio.3003902
UR - https://doi.org/10.1371/journal.pbio.3003902
AB - Pathogenic variants in the genes encoding the non-canonical TGFB signaling components TAK1 (MAP3K7 ) , TAB2 and PKA-Cα (PRKACA) cause rare multisystem disorders, which may include congenital heart disease (CHD). To investigate the role of TAK1 signaling in CHD, we performed genetic analysis of CHD patients and discovered an increased burden of rare TAB2 and TAK1 variants in patients with extracardiac abnormalities. To address the mechanism of TAK1 in heart development, we performed experiments in cell and animal models. Zebrafish tak1 and tab2 mutants presented with cardiac and extracardiac developmental defects, and tak1 mutant hearts showed downregulation of genes encoding core cardiac transcription factors, sarcomeric proteins and extracellular matrix proteins. In vitro experiments indicated that TAK1 via TAB2 and PKA-Cα is activated at the primary cilium during cardiomyogenesis; activation at this site is enhanced by TGFB/BMP ligands. Inactivation of TAK1 inhibited ciliary signaling and cardiomyocyte differentiation, and patient-derived TAK1 variants reduced its ciliary localization. In conclusion, our data establish a pivotal role for TAK1 and its upstream regulators at the primary cilium in heart development and syndromic CHD.
SN - 1544-9173
SN - 1545-7885
ER -