Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells
Open accessAbstract
Chromosome integrity is essential for cell viability and, therefore, highly proliferative cell types require active telomere elongation mechanisms to grow indefinitely. Consistently, deletion of telomerase activity in a genetically modified mouse strain results in growth impairments in all highly proliferative cell populations analyzed so far. We show that telomere attrition dramatically impairs the in vitro proliferation of adult neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of telomerase-deficient adult mice. Reduced proliferation of postnatal neurogenic progenitors was also observed in vivo, in the absence of exogenous mitogenic stimulation. Strikingly, severe telomere erosion resulting in chromosomal abnormalities and nuclear accumulation of p53 did not affect the in vitro proliferative potential of embryonic NSCs. These results suggest that intrinsic differences exist between embryonic and adult neural progenitor cells in their response to telomere shortening, and that some populations of tissue-specific stem cells can bypass DNA damage check points.
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Age-progressive loss of telomere function in mice provokes widespread p53 activation resulting in activation of cellular checkpoints of apoptosis, impaired proliferation and senescence, compromised tissue stem cell and progenitor function, marked tissue atrophy and physiological impairment in many organ systems.
“Of particular relevance to this study, age-progressive loss of telomere function in mice has been shown to provoke widespread p53 activation resulting in activation of cellular checkpoints of apoptosis, impaired proliferation and senescence, compromised tissue stem cell and progenitor function, marked tissue atrophy and physiological impairment in many organ systems 1 , 6 .”
From Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice (2011) · cites this paper as [6]
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Experimental — accuracy not yet measuredNeural stem cells may undergo senescence in vitro in response to various stressors.
“NSCs may undergo senescence in vitro in response to various stressors [178].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [178]
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References 77 · Cited by 152
Research works printed but not linked: 6
- Artandi, S. E., Alson, S., Tietze, M. K., Sharpless, N. E., Ye, S., Greenberg, R. A., Castrillon, D. H., Horner, J. W., Weiler, S. R., Carrasco, R. D. and DePinho, R. A. (2002). Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl. Acad. Sci. USA 99, 8191- 8196.
- Chiu, C. P. and Harley, C. B. (1997). Replicative senescence and cell immortality: the role of telomeres and telomerase. Proc. Soc. Exp. Biol. Med. 214, 99-106.
- Gu, Y., Sekiguchi, J., Gao, Y., Dikkes, P., Frank, K., Ferguson, D., Hasty, P., Chun, J. and Alt, F. W. (2000). Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit- deficient mice. Proc. Natl. Acad. Sci. USA 97, 2668-2673.
- Langley, E., Pearson, M., Faretta, M., Bauer, U. M., Frye, R. A., Minucci, S., Pelicci, P. G. and Kouzarides, T. (2002). Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 21, 2383- 2396.
- Martín-Rivera, L., Herrera, E., Albar, J. P. and Blasco, M. A. (1998). Expression of mouse telomerase catalytic subunit in embryos and adult tissues. Proc. Natl. Acad. Sci. USA 95, 10471-10476.
- Prowse, K. R. and Greider, C. W. (1995). Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc. Natl. Acad. Sci. USA 92, 4818-4822.
- Authors
- Ferrón, S., Mira, H., Franco, S., Cano-Jaimez, M., Bellmunt, E., Ramírez, C., Fariñas, I., & Blasco, M. A.
- Affiliations
- Departamento de Biología Celular, Universidad de Valencia, 46100 Burjassot, Spain
- Universitat de València (ES)
- Spanish National Cancer Research Centre (ES)
- Spanish National Cancer Center (CNIO), 28029 Madrid, Spain
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2004-08-15
- Volume
- 131
- Issue
- 16
- Pages
- 4059-4070
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2154462305
- Cited by
- 152
- References
- 77
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 10 · 2020: 10 · 2019: 2 · 2018: 6 · 2017: 9 · 2016: 4 · 2015: 12 · 2014: 6 · 2013: 11 · 2012: 4
- FWCI
- 5.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundació la Marató de TV3
- European Commission (FIGH-CT-2002-00217)
- Generalitat Valenciana
- Ministerio de Ciencia y Tecnología
- Swiss Bridge Foundation
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- telomere shortening, telomerase deficiency, neural stem cells, chromosomal instability, cell proliferation, subventricular zone, p53 nuclear accumulation, DNA damage checkpoint, neurogenesis
- MeSH terms
- Animals, Brain, Cell Division, Cell Nucleus, Female, Stem Cells, Tumor Suppressor Protein p53, Telomere, Ganglia, Sensory, Mice, Knockout, Telomerase, Chromosomal Instability, Mice
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