TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development
Posted on: 16 August 2024 , updated on: 6 November 2024
Preprint posted on 8 May 2024
Fishing for answers: Zebrafish models show that TAK1 signaling at primary cilia is crucial for heart development.
Selected by Reinier Prosee
Categories: cell biology, developmental biology
Updated 6 November 2024 with a spotLight by Matthew Davies
Background
Primary cilia and heart development
When it comes to cilia, there are three different types. There are the motile cilia which are mainly involved in moving mucus and fluid around in organs like the lungs and brain. You then have the embryonic nodal cilia which are similar to motile cilia but instead of moving back and forth, they move in an anti-clockwise direction and thereby generate a leftward fluid flow. This is critical in development as it directs asymmetric gene expression in the developing embryo. Researchers investigating the link between heart development and cilia have mostly focused on this type of cilia. The authors of this preprint, however, looked at the role of primary cilia in heart development. These cilia are static and mostly involved in signaling.
Clinical studies point out that when there is a disruption in the primary cilia’s signaling function, you end up with a variety of different symptoms including cardiac abnormalities. In this study, the authors used the zebrafish as a model to study this relationship. Despite zebrafish only having two heart chambers instead of four, it is remarkable how similar the actual electrophysiology of the zebrafish heart is when compared to the human heart – in fact, more similar than the mouse heart is to the human heart.
TAK1, TAB2 and heart development
As part of a genetic analysis of patients suffering from a range of heart defects, the gene tab2 was identified. TAB2 is essentially an adapter protein allowing for the activation of TAK1 which in turn leads to downstream signaling as part of the TGF-beta pathway. Before the study highlighted here, TAK1 or TAB2 mutations in zebrafish were already linked to phenotypes observed in patients harbouring similar mutations, including facial, bone and developmental alterations. So the involvement of TAB2 and TAK1 in heart development was perhaps expected, but not really explored until this study.
Key findings of the preprint
TAK1 and TAB2 protein altering variants are linked to syndromic congenital heart disease.
Exome sequencing revealed a significant association between mutations in tak1 and tab2 and syndromic congenital heart disease (sCHD). These variants were found at higher frequencies in sCHD patients compared to controls, while no significant difference was observed in non-syndromic CHD (nsCHD) patients.
tak1 and tab2 mutations cause heart defects in zebrafish
The authors could show that homozygous mutations in tak1 and tab2 cause pericardial edema and atrial ballooning, leading to enlarged hearts. It also caused trabeculation defects and a reduced heart function, with mutants failing to survive past early developmental stages.
tak1 and tab2 mutations cause extra-cardiac abnormalities
The mutant zebrafish studied in this preprint phenocopied patients with a TAK1 or TAB2 protein altering variant. The authors, for example, observed alterations in cartilage affecting the face (making it wider, with the eyes further apart) and fins (corresponding to shorter hands observed in humans). This shows that the zebrafish could help us to understand these specific alterations in more detail.
TAK1 accumulates at the cilia and plays a role in cardiomyogenesis
The authors found that TAK1 accumulates at the cilia during cardiomyogenesis. The development of heart cells is perturbed when TAK1 is mutated. Transfecting cells with two different TAK1 mutations found in human patients led to much lower levels of TAK1 at the cilia. This observation could be replicated in the zebrafish model.
Author summary (in only 3 minutes)
Daniel Baird, co-first author of this preprint, presented this wonderful study during SciCommConnect – a science communication event organised by the community sites of The Company of Biologists. In only three minutes he managed to share the background, main findings and significance of this work in an engaging and accessible way. His talk can be found below – check it out!
doi: https://doi.org/10.1242/prelights.38102
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