AI Insight
This study identifies TAK1 and its regulatory proteins TAB2 and PKA-Cα as critical components operating at the primary cilium to control heart development through non-canonical TGFB/BMP signaling. Researchers found an increased burden of rare TAK1 and TAB2 genetic variants in congenital heart disease patients with additional organ abnormalities, and demonstrated through zebrafish models and cell studies that TAK1 functions at the primary cilium where it is activated by TGFB/BMP ligands to regulate cardiac gene expression and cardiomyocyte differentiation. Patient-derived TAK1 variants showed reduced localization to cilia, directly linking ciliary TAK1 dysfunction to syndromic congenital heart disease.
Why it matters
This research establishes a new mechanism for congenital heart defects involving primary cilia signaling, which could improve genetic diagnosis of syndromic heart disease and identify new therapeutic targets. The findings connect previously known genetic causes of rare multisystem disorders to a specific cellular structure and signaling pathway, potentially enabling more precise medical interventions.
Understand the Science
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, Lars Allan Larsen
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.
Source: TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development