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Telomerase Is Required for Zebrafish Lifespan
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Resumo(s)
Telomerase activity is restricted in humans. Consequentially, telomeres shorten in most cells throughout our lives. Telomere dysfunction in vertebrates has been primarily studied in inbred mice strains with very long telomeres that fail to deplete telomeric repeats during their lifetime. It is, therefore, unclear how telomere shortening regulates tissue homeostasis in vertebrates with naturally short telomeres. Zebrafish have restricted telomerase expression and human-like telomere length. Here we show that first-generation tert-/- zebrafish die prematurely with shorter telomeres. tert-/- fish develop degenerative phenotypes, including premature infertility, gastrointestinal atrophy, and sarcopaenia. tert-/- mutants have impaired cell proliferation, accumulation of DNA damage markers, and a p53 response leading to early apoptosis, followed by accumulation of senescent cells. Apoptosis is primarily observed in the proliferative niche and germ cells. Cell proliferation, but not apoptosis, is rescued in tp53-/-tert-/- mutants, underscoring p53 as mediator of telomerase deficiency and consequent telomere instability. Thus, telomerase is limiting for zebrafish lifespan, enabling the study of telomere shortening in naturally ageing individuals.
Descrição
CMH and MCC are supported by the Portuguese Fundacao para a Ciencia e a Tecnologia (FCT) fellowships. This work was supported by the FCT (PTDC/SAU-ORG/116826/2010 and PTDC/SAU-ONC/116821/2 010) and the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
We indebted to Prisca Chapouton, Susanne Sprungala, and Laure Bally-Cuif for communicating results and sharing reagents prior to publication. We thank Drs. Cuppen and Plasterk (Hubrecht Laboratory) and Dr. Stemple (Welcome Trust Sanger Institute) for providing the zebrafish knockout mutant, which was generated as part of the ZF- MODELS Integrated Project in the 6th Framework Programme (Contract No. LSHG-CT-2003-503496) funded by the European Commission. We are grateful to Joana Nabais, Sofia Esteves, Rita Mateus, Sofia Azevedo, Susana Lopes, and Leonor Saude for help at the initial stages of our work; Tania Carvalho for histopathological analysis; Clara Melo, Graeme Hewitt, and Joao Passos for help with the Telo-FISH. We thank Joao Passos and Lea Harrington for critically reading the manuscript. MGF is a HHMI International Early Career Scientist.
Palavras-chave
DNA-DAMAGE-RESPONSE DYSFUNCTIONAL TELOMERES STEM-CELLS CANCER MICE SENESCENCE APOPTOSIS LENGTH AGE PATHWAYS Ecology, Evolution, Behavior and Systematics Molecular Biology Genetics Genetics(clinical) Cancer Research SDG 3 - Good Health and Well-being