Hippo-Yap/Taz signalling in zebraﬁsh regeneration

npj Regenerative Medicine, 2022 · DOI: https://doi.org/10.1038/s41536-022-00209-8 · Published: January 1, 2022

Genetics Research Methodology & Design Regenerative Medicine & Stem Cells

Simple Explanation

The Hippo pathway is a signaling cascade that regulates cell proliferation, mechanotransduction, stem cell fate, and tumorigenesis. The Hippo pathway effectors Yap/Taz facilitate zebraﬁsh regeneration and that this appears to be latent in mammals. Therapeutically promoting precise and temporal YAP/TAZ signalling in humans may enhance regeneration and hence reduce morbidity. The zebraﬁsh Danio rerio has the potential to completely regenerate multiple adult and embryonic organs, including the heart, ﬁn, and many nervous system compo-nents. The cellular and molecular drivers of zebraﬁsh regeneration have been the subject of intense research. When the Hippo pathway is inactive these phosphorylations do not occur, resulting in YAP1/TAZ nuclear localisation, where they outcompete VGLL4 and bind to transcrip-tion factors TEAD1-4. Binding to TEADs stimulate the expression of a range of pro-proliferative, -oncogenic, -stemness, and -EMT genes, such as CTGF and CYR61.

Study Duration

Not specified

Participants

Zebrafish

Evidence Level

Review Article

Key Findings

1
Hippo pathway effectors Yap/Taz facilitate zebraﬁsh regeneration, suggesting therapeutic potential in promoting YAP/TAZ signaling to enhance mammalian regeneration.
2
Yap1/Taz promote appropriate scar formation and potentially prevent overactivation of the immune response, which, when combined, increase scar resolution, spatio-temporal CM proliferation, and thereby cardiac regeneration.
3
Yap1 senses the mechanical stress caused by SCI, enhancing ctgfa and twist1a expression to activate a pro-EMT and pro-proliferative transcrip-tional programme in ventral ERGs, promoting glial bridging, axon regeneration, and, consequently, functional recovery

Research Summary

This review summarizes the role of the Hippo pathway in zebraﬁsh regeneration, noting that Yap1/Taz signaling often enhances regeneration through promoting cell proliferation, progenitor cell dedifferentiation and maturation, EMT, and scar resolution, and linking to key developmental pathways. The positive effect of Yap1/Taz signalling on regeneration in the zebraﬁsh, which appears to be latent in mammals, suggests some therapeutic potential in promoting YAP/TAZ signalling to enhance mammalian regeneration. The zebraﬁsh is a powerful model system for the study of regeneration due to their rapid external development, relative low cost, transparent juvenile stages and robust reparative regenera-tion as well as the availability of a range of established genetic tools and other experimental procedures to study these.

Practical Implications

Therapeutic Potential for Humans

Promoting precise and temporal YAP/TAZ signaling in humans may enhance regeneration and reduce morbidity.

Cardiac Regeneration Strategies

Pharmacological regulation of the Hippo pathway could modulate CM proliferation and fate plasticity, promoting scarless healing in the adult heart and reducing disease burden.

Spinal Cord Injury Treatment

Enhancing scar resolution, promoting EMT, enhancing CTGF signalling at later stages of regeneration, and identifying CTGF-responsive spinal cord cells may allow for the identiﬁcation of a therapeutic target to promote mammalian spinal cord regeneration.

Study Limitations

1
Increased risk of cancer with enhanced regeneration due to elevated cell proliferation rate, cellular heterogeneity, and increased stemness.
2
Dysregulation of the Hippo pathway and pathological hyperactivation of YAP1/TAZ promotes carcinogenesis in most types of solid tumors.
3
The field of Hippo signaling in the zebraﬁsh is still relatively new, and so much work must be performed to bridge the gaps that are currently preventing its translation to the clinic.

Your Feedback

Was this summary helpful?

Back to Genetics