Congenital heart disease (CHD) remains the most common birth defect and the leading cause of morbidity and mortality in children. Pathogenic variants in TAK1 (MAP3K7), TAB2 and PKA-Cα (PRKACA) cause rare multisystem disorders, including frontometaphyseal dysplasia, cardiospondylocarpofacial syndrome, cardioacrofacial dysplasia, and TAB2 haploinsufficiency syndrome, that frequently include congenital heart defects. Because the hearts of these patients are malformed and functionally impaired, the authors therefore hypothesised that these signalling components play an essential role in heart development.
New findings published in PLOS Biology identify the kinase TAK1 as a key regulator of cardiogenesis operating at the primary cilium in non-canonical TGFB/BMP signalling. This study combines genetic analysis of patient cohorts with molecular, cellular, bioinformatics, and imaging techniques to investigate the role of TAK1 signalling in cardiomyogenesis, mitochondrial-independent energy sensing, and embryonic cardiac development, with implications for genetic heart diseases. Doganli et al. first show an increased burden of rare protein-altering variants in TAK1 and TAB2 in patients with syndromic CHD compared to healthy controls. They used exome sequencing burden analysis, CRISPR-Cas9 mutant zebrafish, RNA sequencing, gastruloids and cell culture experiments to support the model that TAK1, via TAB2 and PKA-Cα, is activated at the primary cilium during cardiomyogenesis, with activation enhanced by TGFB/BMP ligands. Thus, the localisation of TAK1 at the cilium is crucial for downstream cardiogenic signalling.
Zebrafish tak1 or tab2 homozygous mutants displayed heart malformations—enlarged atria, severely reduced ventricular trabeculation, impaired contractility and outflow tract hypoplasia—as well as extracardiac defects in craniofacial structures and pectoral fins, phenocopying the clinical characteristics of human patients. Transcriptomic analyses of mutant hearts highlighted a maturation defect associated with the downregulation of core cardiac transcription factors, sarcomeric proteins, and extracellular matrix genes implicated in CHD. These results show that loss of Tak1 or Tab2 disrupts ciliary signalling and the activation of downstream effectors, including JNK1/2 and SMAD2/3, impairing cardiomyocyte differentiation.
The researchers identified a chain of events linking TAK1, TAB2 and heart malformation. When TAK1 cannot be recruited to the primary cilium, TGFB/BMP signalling is improperly processed. The result is defective myocardial growth and ECM remodelling, as well as the craniofacial and limb anomalies that characterise these multisystem syndromes, providing novel insights into how defects in ciliary signalling cause syndromic CHD.
