The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
Essential role of mouse telomerase in highly proliferative organs
Abstract
We have investigated the role of the enzyme telomerase in highly proliferative organs in successive generations of mice lacking telomerase RNA. Late-generation animals exhibited defective spermatogenesis, with increased programmed cell death (apoptosis) and decreased proliferation in the testis. The proliferative capacity of haematopoietic cells in the bone marrow and spleen was also compromised. These progressively adverse effects coincided with substantial erosion of telomeres (the termini of eukaryotic chromosomes) and fusion and loss of chromosomes. These findings indicate an essential role for telomerase, and hence telomeres, in the maintenance of genomic integrity and in the long-term viability of high-renewal organ systems.
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In the citing paper
“Similarly, in the testes, we observed the previously reported testicular atrophy and associated apoptotic depletion of germ cells in late-generation mTerc -/ -mice (32), with comparable reduction in testes weights ( P = 0.4131) and depletion of germ cells in all three Ink4a / Arf genotypes (Fig. 1 E ).”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [32]
In the citing paper
“Telomerase knock-out (mTERC−/−) mice which carry a homozygous deletion of the RNA component of telomerase (Blasco et al., 1997) show a generation-dependent telomere shortening, which results in critically short telomeres and both senescence and apoptosis (Lee et al., 1998).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Lee et al., 1998
In the citing paper
“In the absence of telomerase, continued cell division results in telomere shortening, loss of ‘capping’ function, and p53 activation12-15.”
From Telomere dysfunction induces metabolic and mitochondrial compromise (2011) · cites this paper as [13]
In the citing paper
“Due to the very long telomeres of Mus musculus, critical reduction in telomere length and chromosomal instability is only seen following extensive passage of mTR−/− cells (Niida et al. 1998”
From p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis (1999) · cites this paper as Lee et al. 1998
In the citing paper
“This induction of p53 coincides with the dramatic increase in apoptosis (as assessed by TUNEL) and decreased cellularity in the G6 mTR−/− testis (Lee et al. 1998”
From p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis (1999) · cites this paper as Lee et al. 1998
In the citing paper
“Loss of telomere function in late-generation (G4 onward) mTR−/− mice has been shown to adversely affect the morphology and physiology of diverse cell types and organ systems (Lee et al. 1998; Rudolph et al. 1999”
From p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis (1999) · cites this paper as Lee et al. 1998
In the citing paper
“In the G6 mTR−/− p53+/− intercrosses, we observed an unusually high rate of productive mating pairs (11 of 22 mating pairs) compared to G6 mTR−/− p53+/+ matings (Lee et al. 1998”
From p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis (1999) · cites this paper as Lee et al. 1998
In the citing paper
“In mTR−/− mice, a decrease in testis size that correlated with germ cell depletion by histology was first evident in G5 mTR−/− animals and became more prevalent in G6 mTR−/− mice (Lee et al. 1998”
From p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis (1999) · cites this paper as Lee et al. 1998
In the citing paper
“In agreement with these findings, studies of telomerase knockout mice revealed short dysfunctional telomeres that profoundly impaired progenitor cell function in actively renewing tissues leading to atrophy and reduced regenerative potential, whereas more quiescent low-turnover tissues such as muscle were unaffected (Allsopp et al., 2003; Lee et al., 1998; Rudolph et al., 1999).”
From Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice (2010) · cites this paper as Lee et al., 1998
In the citing paper
“Of note, late-generation Terc-deficient mice show some signs of accelerated aging (Lee et al., 1998; Rudolph et al., 1999”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Lee et al., 1998
In the citing paper
“Surprisingly, each telomerase component was found to be dispensable for life and these telomerase-knockout mice were remarkably normal (60).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [60]
In the citing paper
“In the G5-G6 TERCÀ/À tissues, there was clear cytogenetic evidence of progressive telomere erosion including 'signal-free' ends, chromosomal end-to-end fusions and anaphase bridging at mitosis (60)(61)(62).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [60]
In the citing paper
“The consequent signalling cascades activate checkpoints that induce either cellular senescence or apoptosis, and in at least some contexts both processes occur simultaneously82,85,91,95.”
From The telomere syndromes (2012) · cites this paper as [85]
In the citing paper
“The telomerase-knockout mouse has provided an important model for understanding telomere-mediated disease mechanisms because there is a remarkable convergence with human disease phenotypes (an overview is shown in Table 2)36,82,84,85,97,99–111.”
From The telomere syndromes (2012) · cites this paper as [85]
In the citing paper
“Although it was initially clear that high-turnover tissues are particularly sensitive to telomere length85,101,112”
From The telomere syndromes (2012) · cites this paper as [85]
In the citing paper
“In addition to promoting cell cycle arrest, dysfunctional telomeres can also activate p53-dependent apoptosis, since mice bearing dysfunctional telomeres show increased apoptosis in proliferative cells31-33.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [31]
In the citing paper
“By the sixth generation (G6), increased apoptosis and compromised function were observed in highly proliferative tissues including skin, hematopoietic and reproductive systems31, 42-44.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [31]
In the citing paper
“and the mice were no longer able to reproduce (15).”
From Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death (1999) · cites this paper as [15]
In the citing paper
“by the seventh generation, highly proliferative organ systems like the testis, bone marrow, and spleen appeared abnormal”
From Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death (1999) · cites this paper as [15]
In the citing paper
“In particular, mice carrying a homozygous germline deletion of the telomerase RNA component gene (Terc−/−) exhibit critically short telomeres and a premature development of age-related pathologies from the second or third generation [8, 18–20, 51, 70, 72, 101, 103]”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [70]
In the citing paper
“telomerase-deficient mice with short telomeres show reduced function of various stem cell compartments including those in the bone marrow and skin 58, 60”
From The common biology of cancer and ageing (2007) · cites this paper as [58]
In the citing paper
“the generation and characterization of the telomerase knockout mouse model has been instrumental in demonstrating that short telomeres result in multiple organismal defects caused by defective tissue regeneration 57, 58, 59”
From The common biology of cancer and ageing (2007) · cites this paper as [58]
In the citing paper
“In stem cell and progenitor cell compartments3–5, TERT serves an important role in keeping telomeres sufficiently long and stable to prevent the adverse consequences of dysfunctional telomeres on cell viability and chromosomal stability6–8.”
From Conditional telomerase induction causes proliferation of hair follicle stem cells (2005) · cites this paper as [7]
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“The first mouse mutant with such a phenotype was defective for the telomerase RNA and displayed progressive telomere shortening for five or six generations prior to the onset of sterility (Lee et al., 1998).”
Age-associated decline of monocyte insulin sensitivity in diabetic and healthy individuals
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Self-citationTelomerase regulation and the intimate relationship with aging
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“Within these cell compartments, telomerase may be important for preventing senescence by maintaining telomere-length integrity in highly proliferative cells, like spermatocytes or hematopoietic stem cells.(42,44,70,73) Some studies have detected telomerase activity, as well as shown age-related declines, in WBCs from…”
InfluentialMouse models in modeling aging and cancer
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“Telomeres are regions of noncoding repetitive nucleotide repeats (TTAGGG) at the ends of chromosomes that protect them from deteriorationduringmitosisor fusionwithneighbouring chromosomes [46,60].”
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“Telomere dysfunction is a primary hallmark of ageing, and there is evidence suggesting that the gut is one of the first tissues to age in a telomerase-dependent manner, with potential consequences for systemic ageing [54, 55, 85].”
BackgroundShort telomeres impede germ cell specification by upregulating MAPK and TGFβ signaling
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Toward Elucidating Epigenetic and Metabolic Regulation of Stem Cell Lineage Plasticity in Skin Aging
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“Telomeres, whose length appears to be crucial in preventing cell senescence (Lundblad & Szostak 1989, Lee et al. 1998), are made of long arrays of short tandem repeats with 39 overhang (Henderson & Blackburn 1989, McElligott & Wellinger 1997).”
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Contributions of Telomere Biology to Human Age-Related Disease
Yang, T.-L., Song, S., & Johnson, F. B. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-411596-5.00007-1 · Cited by 9
Molecular Diagnosis and Precision Therapeutic Approaches for Telomere Biology Disorders
Perona, R., Iarriccio, L., Pintado‐Berninches, L., Rodríguez-Centeno, J., Manguán-García, C., Garcia, E., López‐Ayllón, B. D., & Sastre, L. (2016) · InTech eBooks · doi:10.5772/65353 · Cited by 9
Mathematical model to study the aging of the human follicle according to the telomerase activity
Portillo, A. M., Varela, E., & García-Velasco, J. A. (2018) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2018.11.036 · Cited by 8
Fowler, K. J., Wong, L. H., Griffiths, B., Sibson, M., Reed, S., & Choo, K. H. A. (2004) · Reproduction · doi:10.1530/rep.1.00102 · Cited by 8
“…on a mixed C57BL6/129Sv background were found to have significantly smaller litters than G1 mTR2/2 mice, whereas generation 6 intercrosses exhibited infertility due to a number of factors, including a possible compromise in uterine structure and function (Lee et al. 1998, Herrera et al. 1999a).”
BackgroundTelomere Structure, Function, and Maintenance in Plants
Kim, M. K., & Kim, W. T. (2018) · Journal of Plant Biology · doi:10.1007/s12374-018-0082-y · Cited by 8
Telomeres and telomerase in ageing and cancer
Cowell, J. K. (1999) · AGE · doi:10.1007/s11357-999-0007-2 · Cited by 8
Genetics of Beckwith‐Wiedemann syndrome‐associated tumors: Common genetic pathways
Steenman, M., Westerveld, A., & Mannens, M. M. A. M. (2000) · Genes Chromosomes and Cancer · doi:10.1002/(sici)1098-2264(200005)28:1 · Cited by 105
Wynn, R. F., Cross, M. A., & Testa, N. G. (1998) · British Journal of Haematology · doi:10.1046/j.1365-2141.1998.01092.x · Cited by 8
“…RNA the progressive decline in telomere length results, after four to six generations, in a decrease in clonogenic progenitors in the bone marrow, compromised spermatogenesis, small ovaries and decreased fertility, together with an increase in chromosome fusion and loss (Lee et al, 1998).”
BackgroundThree molecular determinants of malignant conversion and their potential as therapeutic targets
Dome, J. S., & Look, A. T. (1999) · Current Opinion in Oncology · doi:10.1097/00001622-199901000-00013 · Cited by 8
Adaptive and Maladaptive Clonal Hematopoiesis in Telomere Biology Disorders
Lasho, T. L., & Patnaik, M. M. (2023) · Current Hematologic Malignancy Reports · doi:10.1007/s11899-023-00719-2 · Cited by 8
Rap1 and Cdc13 have complementary roles in preventing exonucleolytic degradation of telomere 5′ ends
Runnberg, R., Narayanan, S., & Cohn, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-08663-x · Cited by 8
L’anémone de merNematostella vectensis
Amiel, A., Michel, V., Carvalho, J. E., Shkreli, M., Petit, C., & Röttinger, É. (2021) · médecine/sciences · doi:10.1051/medsci/2020282 · Cited by 7
Berteli, T. S., Wang, F., Kohlrausch, F. B., da Luz, C. M., de Oliveira, F. V., Keefe, D. L., & Navarro, P. A. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07351-y · Cited by 7
“Telomere attrition in oocytes contributes to abnormal meiotic spindles [15] arrested, and fragmented embryos [16], decreased chiasmata and synapsis [17], and infertility [18].”
BackgroundThe Landscape of Telomere Length and Telomerase in Human Embryos at Blastocyst Stage
Wang, F., McCulloh, D. H., Chan, K., Wiltshire, A. M., McCaffrey, C., GRIFO, J. A., & Keefe, D. L. (2023) · Genes · doi:10.3390/genes14061200 · Cited by 7
“Moreover, late-generation mTR−/− mice exhibit an abnormal reproductive phenotype, with severe germ cell depletion [12].”
BackgroundTelomere dysfunction in Tert knockout mice delays BrafV600E ‐induced melanoma development
Zhang, J., Zhang, F., Porter, K. I., Dakup, P., Wang, S., Robertson, G. P., Gaddameedhi, S., & Zhu, J. (2023) · International Journal of Cancer · doi:10.1002/ijc.34713 · Cited by 7
Télomères : un Nobel pour le début de la fin
Rajpar, S., Guittat, L., & Mergny, J. (2011) · Bulletin du Cancer · doi:10.1684/bdc.2011.1378 · Cited by 9
Fukazawa, T., Maeda, Y., Matsuoka, J., Tanaka, N., Tanaka, H., Durbin, M. L., & Naomoto, Y. (2009) · International Journal of Cancer · doi:10.1002/ijc.24584 · Cited by 7
Sy, S. M.-H., Guo, Y., Lan, Y., Ng, H. H. W., & Huen, M. S. Y. (2020) · Translational Oncology · doi:10.1016/j.tranon.2020.100796 · Cited by 7
Genomic instability and aging: Causes and consequences
Gerasymchuk, M. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-85679-9.00028-3 · Cited by 7
Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention
J., D. (2005) · Frontiers in bioscience · doi:10.2741/1707 · Cited by 7
Dyskeratosis congenita: a disorder of telomerase deficiency and its relationship to other diseases
Marrone, A., & Dokal, I. S. (2006) · Expert Review of Dermatology · doi:10.1586/17469872.1.3.463 · Cited by 7
Characterization of ATPase Activity of Recombinant Human Pif1
Huang, Y. S., Zhang, D., & Zhou, J. (2006) · Acta Biochimica et Biophysica Sinica · doi:10.1111/j.1745-7270.2006.00165.x · Cited by 7
Choi, J., Southworth, L. K., Sarin, K. Y., Venteicher, A. S., Ma, W., Chang, W., Cheung, P., Jun, S., Artandi, M. K., Shah, N., et al. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0040010.eor · Cited by 7
Manipulating mouse telomeres: models of tumorigenesis and aging
Xin, Z., & Broccoli, D. (2004) · Cytogenetic and Genome Research · doi:10.1159/000078221 · Cited by 7
“…begin to develop cancer and exhibit certain other pathologies associated with human aging such as hair graying, alopecia, skin lesions, impaired wound healing, cancer, and shortened lifespan (Blasco et al., 1997; Lee et al., 1998; Herrera et al., 1999; Rudolph et al., 1999; Artandi et al., 2000).”
BackgroundResultInfluentialThe Evolution of Mouse Models of Cancer: Past, Present, and FuturePreprint
Abate-Shen, C. T., & Politi, K. A. (2024) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041736 · Cited by 7
Nitric Oxide–Asymmetric Dimethylarginine System in Endothelial Cell Senescence
Scalera, F., & Bode‐Böger, S. M. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-373866-0.00014-9 · Cited by 6
Wang, D.-X., Zhu, X., Ma, X.-R., Wang, L., Dong, Z.-J., Lin, R., Cao, Y., & Zhao, J. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.726345 · Cited by 6
Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline
Graniel, J. V., Bisht, K. K., Friedman, A. D., White, J. S., Perkey, E., Vanderbeck, A., Moroz, A., Carrington, L. J., Brandstadter, J. D., Allen, F., et al. (2021) · Life Science Alliance · doi:10.26508/lsa.202101208 · Cited by 7
“The reproductive defects observed for TPP1 K82Δ are reminiscent of sterility observed in acd/acd hypomorphic mice (Keegan et al. 2005) and late-generation mTR-/- mice (Lee et al. 1998; Hemann et al. 2001).”
BackgroundResultInfluentialInfluence of atmospheric circulation variations on the ozone layer
Jadin, E. A., Kondratyev, K. Y., Bekoriukov, V. I., & Vargin, P. N. (2005) · International Journal of Remote Sensing · doi:10.1080/01431160500076541 · Cited by 6
Zhang, L., Li, S., Chen, L., Li, J., Zhang, Z., Yang, Y., Wang, X., & Liu, J. (2019) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-180876 · Cited by 6
“…telomerase is to sustain telomere length by adding telomeric repeats onto the ends of linear chromosomes, which is a crucial process for preventing cell growth arrest and cellular replicative senescence caused by critically short telomeres (Harley et al., 1990; Kim et al., 1994; Lee et al., 1998).”
RetractedCallén, E., Ramı́rez, M. J., Creus, A., Marcos, R., Ortega, J., Olivé, T., Badell, I., & Surrallés, J. (2002) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(02)00081-7 · Cited by 6
GAMETOGENESIS '98 Male Infertility and the Genetics of Spermatogenesis
Okabe, M., Ikawa, M., & Ashkenas, J. (1998) · Cited by 6
Fertility, IVF and reproductive genetics
Varela, E., Sánchez-de-Puerta, I., & García-Velasco, J. A. (2018) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/gco.0000000000000456 · Cited by 6
Yokoyama, Y., Wan, X., Takahashi, Y., Shinohara, A., Liulin, T., & Tamaya, T. (2002) · Archives of Biochemistry and Biophysics · doi:10.1016/s0003-9861(02)00284-9 · Cited by 6
Telomeres and Cell Division Potential
Perrem, K., & Reddel, R. R. (1999) · Progress in molecular and subcellular biology · doi:10.1007/978-3-662-06227-2_8 · Cited by 6
Sornapudi, T. R., Yuan, L., Braunger, J. M., Uhler, C., & Shivashankar, G. V. (2024) · Molecular Biology of the Cell · doi:10.1091/mbc.e24-09-0430 · Cited by 5
“Aging is inevitable and accompanied by various alterations including the accumulation of DNA damage (Rossi et al., 2007), telomere attrition (Lee et al., 1998), increased reactive oxygen production and mitochondrial dysfunction, which ultimately leads to the loss of cellular function and cell cycle…”
Baliou, S., Spanakis, M., Apetroaei, M.-M., Ιωάννου, Π., Fragkiadaki, P., Fragkiadoulaki, I., Renieri, E. A., Vakonaki, E., Tzatzarakis, M. N., Nosyrev, A. E., et al. (2025) · World Academy of Sciences Journal · doi:10.3892/wasj.2025.344 · Cited by 6
Allen (1999) · doi:10.1002/(sici)1097-4652(199907)180:1
Epstein-Barr virus-dependent lymphoproliferative disease: critical role of IL-6
(2000) · Pure Amsterdam UMC · doi:10.1002/1521-4141(200007)30:7 · Cited by 1
Metadata
- Authors
- Lee, H.-W., Blasco, M. A., Gottlieb, G. J., Horner, J. W., Greider, C. W., & DePinho, R. A.
- Affiliations
- Albert Einstein College of Medicine (US)
- Quest Diagnostics (United States) (US)
- Johns Hopkins University (US)
- Venue
- Nature
- Published
- 1998-04
- Volume
- 392
- Issue
- 6676
- Pages
- 569-574
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1612842202
- Cited by
- 1,270
- References
- 40
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 23 · 2023: 24 · 2022: 25 · 2021: 40 · 2020: 25 · 2019: 30 · 2018: 38 · 2017: 26 · 2016: 40 · 2015: 45 · 2014: 31 · 2013: 42 · 2012: 49
- FWCI
- 45.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Keywords
- telomerase, telomeres, spermatogenesis, apoptosis, cell proliferation, testis, hematopoietic cells, bone marrow, spleen, chromosome fusion, chromosome loss, genome stability, tissue renewal, mice
- MeSH terms
- Animals, Cell Division, Chromosome Banding, Female, Embryonic and Fetal Development, Hematopoiesis, Hematopoietic Stem Cells, Lymphocytes, Male, Mice, Inbred C57BL, Ovary, Testis, Telomere, Apoptosis, Telomerase, Mice
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