DNA-damage induced cell death in yap1;wwtr1 mutant epidermal basal cells
In a previous study, it was reported that Yap1 and Wwtr1 in zebrafish regulates the morphogenesis of the posterior body and epidermal fin fold (Kimelman, D., et al. 2017). We report here that DNA damage induces apoptosis of epidermal basal cells (EBCs) in zebrafish yap1-/-;wwtr1-/- embryos. Specifically, these mutant EBCs exhibit active Caspase-3, Caspase-8 and γH2AX, consistent with DNA damage serving as a stimulus of the extrinsic apoptotic pathway in epidermal cells. Live imaging of zebrafish epidermal cells reveals a steady growth of basal cell size in the developing embryo, but this growth is inhibited in mutant basal cells followed by apoptosis, leading to the hypothesis that factors underscoring cell size play a role in this DNA damage-induced apoptosis phenotype. We tested two of these factors using cell stretching and substrate stiffness assays, and found that HaCaT cells cultured on stiff substrates exhibit more numerous γH2AX foci compared to ones cultured on soft substrates. Thus, our experiments suggest that substrate rigidity may modulate genomic stress in epidermal cells, and that Yap1 and Wwtr1 promotes their survival.
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1, 3, 4, 5 and 6.
Article and author information
Ministry of Education - Singapore (MOE2016-T3-1-002)
- Jason KH Lai
- Pearlyn JY Toh
- Hamizah A Cognart
- Timothy E Saunders
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All zebrafish husbandry was performed under standard conditions in accordance with institutional (Biological Resource Center, A*Star, Singapore, and Tata Institute of Fundamental Research, India) and national ethical and animal welfare guidelines (Singapore IACUC: 181323 and GMAC: Res-21-034). All users were trained in ethical handling of zebrafish.
- Marianne E Bronner, California Institute of Technology, United States
- Preprint posted: July 23, 2021 (view preprint)
- Received: July 23, 2021
- Accepted: May 29, 2022
- Accepted Manuscript published: May 30, 2022 (version 1)
- Accepted Manuscript updated: May 31, 2022 (version 2)
- Version of Record published: June 14, 2022 (version 3)
© 2022, Lai et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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