Telomerase is Required for Zebrafish Lifespan

Overview

Journal PLoS Genet

Specialty Genetics

Date 2013 Jan 26

PMID 23349637

Citations 60

Authors

Catarina M Henriques

Madalena C Carneiro

Ines M Tenente

Antonio Jacinto

Miguel Godinho Ferreira

Affiliations

Soon will be listed here.

Abstract

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.

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References

Liew W, Bartfai R, Lim Z, Sreenivasan R, Siegfried K, Orban L . Polygenic sex determination system in zebrafish. PLoS One. 2012; 7(4):e34397. PMC: 3323597. DOI: 10.1371/journal.pone.0034397. View

Kishi S, Bayliss P, Uchiyama J, Koshimizu E, Qi J, Nanjappa P . The identification of zebrafish mutants showing alterations in senescence-associated biomarkers. PLoS Genet. 2008; 4(8):e1000152. PMC: 2515337. DOI: 10.1371/journal.pgen.1000152. View

Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov J . Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol. 2012; 14(4):355-65. PMC: 3717580. DOI: 10.1038/ncb2466. View

Roos W, Kaina B . DNA damage-induced cell death by apoptosis. Trends Mol Med. 2006; 12(9):440-50. DOI: 10.1016/j.molmed.2006.07.007. View

Ozaki Y, Saito K, Shinya M, Kawasaki T, Sakai N . Evaluation of Sycp3, Plzf and Cyclin B3 expression and suitability as spermatogonia and spermatocyte markers in zebrafish. Gene Expr Patterns. 2011; 11(5-6):309-15. DOI: 10.1016/j.gep.2011.03.002. View

Flores I, Blasco M . A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres. PLoS One. 2009; 4(3):e4934. PMC: 2654505. DOI: 10.1371/journal.pone.0004934. View

Rog O, Miller K, Ferreira M, Cooper J . Sumoylation of RecQ helicase controls the fate of dysfunctional telomeres. Mol Cell. 2009; 33(5):559-69. DOI: 10.1016/j.molcel.2009.01.027. View

Wienholds E, Plasterk R . Target-selected gene inactivation in zebrafish. Methods Cell Biol. 2004; 77:69-90. DOI: 10.1016/s0091-679x(04)77004-1. View

Campisi J, Sedivy J . How does proliferative homeostasis change with age? What causes it and how does it contribute to aging?. J Gerontol A Biol Sci Med Sci. 2009; 64(2):164-6. PMC: 2655008. DOI: 10.1093/gerona/gln073. View

10.

Wright W, Shay J . Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nat Med. 2000; 6(8):849-51. DOI: 10.1038/78592. View

11.

Forsyth N, Wright W, Shay J . Telomerase and differentiation in multicellular organisms: turn it off, turn it on, and turn it off again. Differentiation. 2002; 69(4-5):188-97. DOI: 10.1046/j.1432-0436.2002.690412.x. View

12.

Wienholds E, van Eeden F, Kosters M, Mudde J, Plasterk R, Cuppen E . Efficient target-selected mutagenesis in zebrafish. Genome Res. 2003; 13(12):2700-7. PMC: 403812. DOI: 10.1101/gr.1725103. View

13.

Kimura M, Stone R, Hunt S, Skurnick J, Lu X, Cao X . Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths. Nat Protoc. 2010; 5(9):1596-607. DOI: 10.1038/nprot.2010.124. View

14.

Berghmans S, Murphey R, Wienholds E, Neuberg D, Kutok J, Fletcher C . tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors. Proc Natl Acad Sci U S A. 2005; 102(2):407-12. PMC: 544293. DOI: 10.1073/pnas.0406252102. View

15.

Sahin E, DePinho R . Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature. 2010; 464(7288):520-8. PMC: 3733214. DOI: 10.1038/nature08982. View

16.

Kim N, Piatyszek M, Prowse K, Harley C, WEST M, Ho P . Specific association of human telomerase activity with immortal cells and cancer. Science. 1994; 266(5193):2011-5. DOI: 10.1126/science.7605428. View

17.

Davidson A, Zon L . The 'definitive' (and 'primitive') guide to zebrafish hematopoiesis. Oncogene. 2004; 23(43):7233-46. DOI: 10.1038/sj.onc.1207943. View

18.

Greider C, Blackburn E . Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985; 43(2 Pt 1):405-13. DOI: 10.1016/0092-8674(85)90170-9. View

19.

Erdmann N, Liu Y, Harrington L . Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice. Proc Natl Acad Sci U S A. 2004; 101(16):6080-5. PMC: 395926. DOI: 10.1073/pnas.0401580101. View

20.

Choudhury A, Ju Z, Djojosubroto M, Schienke A, Lechel A, Schaetzlein S . Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet. 2006; 39(1):99-105. DOI: 10.1038/ng1937. View