Publication: Premature aging in telomerase-deficient zebrafish
Authors
Anchelin, Monique ; Alcaráz Pérez, Francisca ; Bernabé García, Manuel ; Cayuela, María L. ; Martínez Cáceres, Carlos Manuel ; Mulero Méndez, Victoriano Francisco
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Publisher
The Company of Biologists
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DOI
https://doi.org/10.1242/dmm.011635
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info:eu-repo/semantics/article
Description
© 2013. Published by The Company of Biologists Ltd. This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by/4.0/
This document is the Published version of a Published Work that appeared in final form in Disease Models & Mechanism. To access the final edited and published work see https://doi.org/10.1242/dmm.011635
Abstract
The study of telomere biology is crucial to the understanding of aging and cancer. In the pursuit of greater knowledge in the field of human telomere biology, the mouse has been used extensively as a model. However, there are fundamental differences between mouse and human cells. Therefore, additional models are required. In light of this, we have characterized telomerase-deficient zebrafish (Danio rerio) as the second vertebrate model for human telomerase-driven diseases. We found that telomerase-deficient zebrafish show p53-dependent premature aging and reduced lifespan in the first generation, as occurs in humans but not in mice, probably reflecting the similar telomere length in fish and humans. Among these aging symptoms, spinal curvature, liver and retina degeneration, and infertility were the most remarkable. Although the second-generation embryos died in early developmental stages, restoration of telomerase activity rescued telomere length and survival, indicating that telomerase dosage is crucial. Importantly, this model also reproduces the disease anticipation observed in humans with dyskeratosis congenita (DC). Thus, telomerase haploinsufficiency leads to anticipation phenomenon in longevity, which is related to telomere shortening and, specifically, with the proportion of short telomeres. Furthermore, p53 was induced by telomere attrition, leading to growth arrest and apoptosis. Importantly, genetic inhibition of p53 rescued the adverse effects of telomere loss, indicating that the molecular mechanisms induced by telomere shortening are conserved from fish to mammals. The partial rescue of telomere length and longevity by restoration of telomerase activity, together with the feasibility of the zebrafish for high-throughput chemical screening, both point to the usefulness of this model for the discovery of new drugs able to reactivate telomerase in individuals with DC.
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Citation
Disease Models & Mechanism, 2013, Vol. 6 (5), pp. 1101-1112
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Este ítem está sujeto a una licencia Creative Commons. http://creativecommons.org/licenses/by/4.0/