TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development

Canan Doganli, Daniel A. Baird, Yeasmeen Ali, Oskar Kaaber Thomsen, Enrique Audain, Line 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

Posted on: 16 August 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

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!

Tags: #scicomm, development, heart, signaling, talk, tgf beta, zebrafish

doi: https://doi.org/10.1242/prelights.38102

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Author's response

Daniel A Baird shared

What’s next for this story?

RNA sequencing analysis of human patient samples showed that there are quite a lot of genes that are downregulated when you mutate TAK1. Now some of these genes are involved in the extracellular matrix, which we already know plays a major role in atrial chamber development and in the general functioning of the heart. Also, it influences trabeculation. All these things were also affected in our zebrafish mutants, but at this point we don’t actually know whether there are less extracellular matrix proteins in the mutant zebrafish. We just know that the genes are downregulated. So I think the next part of this story could zoom in on the role of the extracellular matrix in heart development and its relationship to TAB2 and TAK1.

Another interesting thing is that TAK1 isn’t just activated by TAB2. It can also be activated by PKA, involved in Hedgehog signaling. It brings into question what the possible role of cross-talk between different signaling pathways could be in heart development.

How has the field reacted to the findings presented in this preprint?

There was quite some excitement just before it was posted as a preprint. It was when I gave a talk at the UK cilia meeting in Edinburgh. Canan Doganli, who was the main driver behind the project, has received a lot of interest about the project whenever she’s presented it at meetings. More recently my colleague Oskar travelled to a meeting in the US where it also got quite a lot of interest from the cilia community. Mostly, people are interested in seeing how this been quite excited by the confirmation of the involvement of a specific gene in the TGF-beta signaling pathway in heart development. Also, they are excited about the implications of these findings – and our model system – in a more clinical setting.

When I presented the project as a poster at the Weinstein Cardiovascular Development & Regeneration 2023 conference in San Diego, I won one of the poster prizes at the conference, highlighting that the field was excited by the findings.

Could you elaborate on how your findings in zebrafish could be translated to a more clinical setting?

We see potential in using our zebrafish mutants as a model to further explore the relationship between primary cilia signaling and heart development abnormalities, especially in relation to extracardiac defects. While gene therapy could be one thing to explore in this model, a more realistic option is drug screening. We could potentially use zebrafish to identify treatments that alleviate symptoms of heart conditions in human patients.

Although still in the early stages, we’re exploring the idea of humanizing zebrafish by introducing patient-specific mutations into them to observe how those genetic changes manifest in the model. This approach could offer valuable insights into disease mechanisms and potential therapies.

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