The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
Open accessAbstract
Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells. It has been proposed that this is at least partially caused by the senescence of progenitors with age; however, it has not yet been tested whether genes associated with senescence functionally contribute to physiological declines in progenitor activity. Here we show that progenitor proliferation in the subventricular zone and neurogenesis in the olfactory bulb, as well as multipotent progenitor frequency and self-renewal potential, all decline with age in the mouse forebrain. These declines in progenitor frequency and function correlate with increased expression of p16INK4a, which encodes a cyclin-dependent kinase inhibitor linked to senescence. Ageing p16INK4a-deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16INK4a deficiency did not detectably affect progenitor function in the dentate gyrus or enteric nervous system, indicating regional differences in the response of neural progenitors to increased p16INK4a expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16INK4a expression.
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In the citing paper
“The NPC defect that we discovered is partly regulated by Cdkn2a, a central component of aging responsible for decreased neurogenesis and differentiation of NPCs (Abdouh et al., 2012; Molofsky et al., 2006).”
From Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model (2022) · cites this paper as Molofsky et al., 2006
Experimental — accuracy not yet measuredIn the citing paper
“Age-dependent reduction in stem cell number or perturbed cell-cycle activity has been reported in skeletal muscle stem cells, neural stem cells and germline stem cells110, 120–122.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [121]
In the citing paper
“other tumor suppressors (e.g., p16Ink4a) which appear to suppress cancer at the cost of tissue resident stem cells and therefore may contribute to decreased regenerative potential during the aging process (Krishnamurthy et al., 2006; Molofsky et al., 2006).”
From FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis (2009) · cites this paper as Molofsky et al., 2006
In the citing paper
“Because several studies have established a role for the polycomb group protein Bmi1 in the regulation of p16Ink4a (26–28), we analyzed the levels of Bmi1.”
From Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice (2009) · cites this paper as [28]
In the citing paper
“age-induced expression of p16INK4a in adult stem cells seems to be associated with widespread impairment in tissue regeneration 23, 24, 25”
From The common biology of cancer and ageing (2007) · cites this paper as [25]
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Cites
Subventricular zone astrocytes are neural stem cells in the adult mammalian brain
Doetsch, F., Caillé, I., Lim, D. A., García-Verdugo, J. M., & Alvarez-Buylla, A. (1999) · Cell · doi:10.1016/s0092-8674(00)80783-7 · Cited by 3,898
Kuhn, H., Dickinson-Anson, H., & Gage, F. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-06-02027.1996 · Cited by 3,139
Functional neurogenesis in the adult hippocampus
van Praag, H., Schinder, A. F., Christie, B. R., Toni, N., Palmer, T. D., & Gage, F. H. (2002) · Nature · doi:10.1038/4151030a · Cited by 2,853
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,379
Rejuvenation of aged progenitor cells by exposure to a young systemic environment
Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005) · Nature · doi:10.1038/nature03260 · Cited by 2,287
BRAFE600-associated senescence-like cell cycle arrest of human naevi
Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., & Peeper, D. S. (2005) · Nature · doi:10.1038/nature03890 · Cited by 2,160
Identification of a Neural Stem Cell in the Adult Mammalian Central Nervous System
Johansson, C. B., Momma, S., Clarke, D. L., Risling, M., Lendahl, U., & Frisén, J. (1999) · Cell · doi:10.1016/s0092-8674(00)80956-3 · Cited by 1,875
Jacobs, J. J. L., Kieboom, K., Marino, S., DePinho, R. A., & van Lohuizen, M. (1999) · Nature · doi:10.1038/16476 · Cited by 1,580
Ink4a/Arf expression is a biomarker of aging
Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22475 · Cited by 1,486
Self-citationBmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation
Molofsky, A. V., Pardal, R., Iwashita, T., Park, I.-K., Clarke, M. F., & Morrison, S. J. (2003) · Nature · doi:10.1038/nature02060 · Cited by 1,317
Self-citationNotch-Mediated Restoration of Regenerative Potential to Aged Muscle
Conboy, I. M., Conboy, M. J., Smythe, G. M., & Rando, T. A. (2003) · Science · doi:10.1126/science.1087573 · Cited by 1,121
DNA Repair, Genome Stability, and Aging
Lombard, D. B., Chua, K. F., Mostoslavsky, R., Franco, S., Gostissa, M., & Alt, F. W. (2005) · Cell · doi:10.1016/j.cell.2005.01.028 · Cited by 944
The aging of hematopoietic stem cells
Morrison, S. J., Wandycz, A. M., Akashi, K., Globerson, A., & Weissman, I. L. (1996) · Nature Medicine · doi:10.1038/nm0996-1011 · Cited by 853
Self-citationLoss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis
Sharpless, N. E., Bardeesy, N., Lee, K.-H., Carrasco, D., Castrillon, D. H., Aguirre, A. J., Wu, E. A., Horner, J. W., & DePinho, R. A. (2001) · Nature · doi:10.1038/35092592 · Cited by 848
Self-citationTumor suppression by Ink4a-Arf: progress and puzzles.
Lowe, S. W., & Sherr, C. J. (2003) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00013-8 · Cited by 699
LeX/ssea-1 Is Expressed by Adult Mouse CNS Stem Cells, Identifying Them as Nonependymal
Capela, A., & Temple, S. (2002) · Neuron · doi:10.1016/s0896-6273(02)00835-8 · Cited by 671
Molofsky, A. V., He, S., Bydon, M., Morrison, S. J., & Pardal, R. (2005) · Genes & Development · doi:10.1101/gad.1299505 · Cited by 599
Self-citationZindy, F., Quelle, D. E., Roussel, M. F., & Sherr, C. J. (1997) · Oncogene · doi:10.1038/sj.onc.1201178 · Cited by 574
Enwere, E. K., Shingo, T., Gregg, C., Fujikawa, H., Ohta, S., & Weiss, S. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2751-04.2004 · Cited by 549
Crane, G. M., Mosher, J. T., Bixby, S., Joseph, N. M., Iwashita, T., & Morrison, S. J. (2002) · Neuron · doi:10.1016/s0896-6273(02)00827-9 · Cited by 543
Self-citationChiasson, B. J., Tropepe, V., Morshead, C. M., & van der Kooy, D. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-11-04462.1999 · Cited by 529
Maslov, A. Y., Barone, T. A., Plunkett, R. J., & Pruitt, S. C. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4608-03.2004 · Cited by 522
Bruggeman, S. W. M., Valk-Lingbeek, M. E., van der Stoop, P. P. M., Jacobs, J. J. L., Kieboom, K., Tanger, E., Hulsman, D., Leung, C., Arsenijevic, Y., Marino, S., et al. (2005) · Genes & Development · doi:10.1101/gad.1299305 · Cited by 315
de Haan, G., NIJHOF, W., & Zant, G. E. V. (1997) · Blood · doi:10.1182/blood.v89.5.1543 · Cited by 300
The aging of lympho-hematopoietic stem cells
Geiger, H., & Van Zant, G. (2002) · Nature Immunology · doi:10.1038/ni0402-329 · Cited by 233
The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis
Sharpless, N. E., Ramsey, M. R., Balasubramanian, P., Castrillon, D. H., & DePinho, R. A. (2004) · Oncogene · doi:10.1038/sj.onc.1207074 · Cited by 224
Self-citationImmunohistochemical survey of p16INK4A expression in normal human adult and infant tissues.
Nielsen, G. P., Stemmer-Rachamimov, A. O., Shaw, J., Roy, J. E., Koh, J., & Louis, D. N. (1999) · PubMed · Cited by 169
Chien, K. R., & Karsenty, G. (2005) · Cell · doi:10.1016/j.cell.2005.02.006 · Cited by 143
Increased gene dosage of Ink4a/Arf results in cancer resistance and normal agingPreprint
Matheu, A., Pantoja, C., Efeyan, A., Criado, L. M., Martín‐Caballero, J., Flores, J. M., Klatt, P., & Serrano, M. (2004) · Genes & Development · doi:10.1101/gad.310304 · Cited by 140
Genetic regulation of primitive hematopoietic stem cell senescence
Chen, J., Astle, C. M., & Harrison, D. E. (2000) · Experimental Hematology · doi:10.1016/s0301-472x(99)00157-5 · Cited by 131
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López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
“A similar functional attrition of stem cells has been found in essentially all adult stem cell compartments, including the mouse forebrain (Molofsky et al., 2006), the bone (Gruber et al.”
BackgroundThe senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
Jones, P. A., & Baylin, S. B. (2007) · Cell · doi:10.1016/j.cell.2007.01.029 · Cited by 4,515
“Recent studies of knockout mice have revealed that germline loss of this gene increases stem cell life span (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006), consistent with a proposed role in tumorigenesis for facilitating early abnormal clonal expansion of cells at risk for cancer.”
BackgroundCellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
Cell cycle, CDKs and cancer: a changing paradigm
Malumbres, M., & Barbacid, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2602 · Cited by 3,957
Metadata
- Authors
- Molofsky, A. V., Slutsky, S. G., Joseph, N. M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N. E., & Morrison, S. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Morrison, Sean J.
- ORCID
- Venue
- Nature
- Published
- 2006-09
- Volume
- 443
- Issue
- 7110
- Pages
- 448-452
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2586960
- OpenAlex
- W2065564965
- Cited by
- 972
- References
- 30
- Citations by year
- 2026: 12 · 2025: 25 · 2024: 18 · 2023: 23 · 2022: 43 · 2021: 37 · 2020: 39 · 2019: 47 · 2018: 47 · 2017: 55 · 2016: 41 · 2015: 48 · 2014: 53 · 2013: 60 · 2012: 54
- FWCI
- 23.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Ellison Medical Foundation
- Sidney Kimmel Foundation for Cancer Research
- Sidney Kimmel Foundation
- National Institutes of Health
- National Institute on Aging (R01AG024945)
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- 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
- Keywords
- p16INK4a, cellular senescence, aging, neurogenesis, subventricular zone, olfactory bulb, multipotent progenitors, stem cell self-renewal, tumour suppressor, cyclin-dependent kinase inhibitors, type 2 diabetes, pancreatic islet regeneration
- MeSH terms
- Aging, Animals, Neurons, Olfactory Bulb, Regeneration, Stem Cells, Prosencephalon, Cyclin-Dependent Kinase Inhibitor p16, Cell Proliferation, Mice
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