Expression and regulation of antioxidant enzymes in the developing limb support a function of ROS in interdigital cell death
Open accessAbstract
Vertebrate limb development is a well-studied model of apoptosis; however, little is known about the intracellular molecules involved in activating the cell death machinery. We have shown that high levels of reactive oxygen species (ROS) are present in the interdigital 'necrotic' tissue of mouse autopod, and that antioxidants can reduce cell death. Here, we determined the expression pattern of several antioxidant enzymes in order to establish their role in defining the areas with high ROS levels. We found that the genes encoding the superoxide dismutases and catalase are expressed in autopod, but they are downregulated in the interdigital regions at the time ROS levels increased and cell death was first detected. The possible role of superoxide and/or peroxide in activating cell death is supported by the protective effect of a superoxide dismutase/catalase mimetic. Interestingly, we found that peroxidase activity and glutathione peroxidase-4 gene (Gpx4) expression were restricted to the non-apoptotic tissue (e.g., digits) of the developing autopod. Induction of cell death with retinoic acid caused an increase in ROS and decrease in peroxidase activity. Even more inhibition of glutathione peroxidase activity leads to cell death in the digits, suggesting that a decrease in antioxidant activity, likely due to Gpx4, caused an increase in ROS levels, thus triggering apoptosis.
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In interdigital dying tissues, apoptotic markers are present, ROS levels are elevated, and Gpx4 expression is reduced, suggesting ferroptosis activation.
“In addition to the presence of apoptotic markers in these interdigital dying tissues, ROS levels are elevated and Gpx4 expression levels are reduced, suggesting activation of ferroptosis [48].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [48]
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Ferroptosis: Death by Lipid Peroxidation
Yang, W. S., & Stockwell, B. R. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.10.014 · Cited by 3,088 · see citing works
- Authors
- Schnabel, D., Salas-Vidal, E., Narváez, V., del Rayo Sánchez-Carbente, M., Hernández-García, D., Cuervo, R., & Covarrubias, L.
- Affiliations
- Universidad Nacional Autónoma de México (MX)
- Corresponding author
- Covarrubias, Luis
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2006-03
- Volume
- 291
- Issue
- 2
- Pages
- 291-299
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W1999062352
- Cited by
- 78
- References
- 51
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 4 · 2015: 6 · 2014: 6 · 2013: 4
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- reactive oxygen species, interdigital cell death, apoptosis, antioxidant enzymes, superoxide dismutase, catalase, GPX4, autopod, limb development, retinoic acid, peroxidase activity, superoxide, gene expression regulation
- MeSH terms
- Animals, Catalase, Extremities, Glutathione Peroxidase, RNA, Messenger, Superoxide Dismutase, Tretinoin, Apoptosis, Reactive Oxygen Species, Gene Expression Regulation, Developmental, Mice
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