Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells
Open accessAbstract
Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreER T2 /R26R-YFP/Notch1 loxP/loxP [Notch1inducible knock-out (iKO)] mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFP+ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild-type (WT) mice (nestin-CreER T2 /R26R-YFP/Notch1 w/w ) after tamoxifen (post-TAM), producing adult-generated YFP+ dentate gyrus neurons. Compared with WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFP+ cells 13 and 30 d post-TAM but had significantly fewer SGZ YFP+ cells 60 and 90 d post-TAM. Significantly fewer YFP+ Type-1 NSCs and transiently amplifying progenitors (TAPs) resulted in generation of fewer YFP+ granule neurons in Notch1 iKO mice. Strikingly, 30 d of running rescued this deficit, as the total YFP+ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch- and Type-1 NSC-independent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli.
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After deletion of Notch1, running is unable to rescue the decrease in stem cells in the dentate gyrus, despite a large increase of neurogenesis.
“Conversely, after deletion of the quiescence-maintaining gene Notch1, which reduces the number of stem cells in the dentate gyrus, running is unable to rescue this decrease, despite the large increase of neurogenesis (Ables et al., 2010).”
From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as Ables et al., 2010
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Cites
Notch Signaling: Cell Fate Control and Signal Integration in Development
Artavanis-Tsakonas, S., Rand, M. D., & Lake, R. J. (1999) · Science · doi:10.1126/science.284.5415.770 · Cited by 5,909 · see citing works
Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus
van Praag, H., Kempermann, G., & Gage, F. H. (1999) · Nature Neuroscience · doi:10.1038/6368 · Cited by 3,880 · see citing works
Mechanisms and Functional Implications of Adult Neurogenesis
Zhao, C., Deng, W., & Gage, F. H. (2008) · Cell · doi:10.1016/j.cell.2008.01.033 · Cited by 3,007 · see citing works
Running enhances neurogenesis, learning, and long-term potentiation in mice
van Praag, H., Christie, B. R., Sejnowski, T. J., & Gage, F. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.23.13427 · Cited by 2,904 · see citing works
ADULT NEUROGENESIS IN THE MAMMALIAN CENTRAL NERVOUS SYSTEM
Ming, G., & Song, H. (2005) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.28.051804.101459 · Cited by 1,829 · see citing works
Milestones of neuronal development in the adult hippocampus
Kempermann, G., Jessberger, S., Steiner, B., & Kronenberg, G. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.05.013 · Cited by 1,411 · see citing works
Deficient T Cell Fate Specification in Mice with an Induced Inactivation of Notch1
Radtke, F., Wilson, A., Stark, G., Bauer, M., van Meerwijk, J. P. M., MacDonald, H. R., & Aguet, M. (1999) · Immunity · doi:10.1016/s1074-7613(00)80054-0 · Cited by 1,393 · see citing works
Self-citationRoles of continuous neurogenesis in the structural and functional integrity of the adult forebrain
Imayoshi, I., Sakamoto, M., Ohtsuka, T., Takao, K., Miyakawa, T., Yamaguchi, M., Mori, K., Ikeda, T., Itohara, S., & Kageyama, R. (2008) · Nature Neuroscience · doi:10.1038/nn.2185 · Cited by 1,054 · see citing works
Notch signalling regulates stem cell numbers in vitro and in vivo
Androutsellis‐Theotokis, A., Leker, R. R., Soldner, F., Hoeppner, D. J., Ravin, R., Poser, S., Rueger, M. A., Bae, S., Kittappa, R., & McKay, R. D. G. (2006) · Nature · doi:10.1038/nature04940 · Cited by 952 · see citing works
VEGF is necessary for exercise‐induced adult hippocampal neurogenesis
Fabel, K., Fabel, K., Tam, B., Kaufer, D., Baiker, A., Simmons, N., Kuo, C. J., & Palmer, T. D. (2003) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2003.03041.x · Cited by 861 · see citing works
Suh, H., Consiglio, A., Ray, J., Sawai, T., D’Amour, K. A., & Gage, F. H. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.09.002 · Cited by 818 · see citing works
Imayoshi, I., Sakamoto, M., Yamaguchi, M., Mori, K., & Kageyama, R. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4987-09.2010 · Cited by 716 · see citing works
Lugert, S., Basak, O., Knuckles, P., Haussler, U., Fabel, K., Götz, M., Haas, C. A., Kempermann, G., Taylor, V., & Giachino, C. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.03.017 · Cited by 704 · see citing works
Neurogenesis and Exercise: Past and Future Directions
van Praag, H. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8028-z · Cited by 645 · see citing works
Kronenberg, G., Reuter, K., Steiner, B., Brandt, M. D., Jessberger, S., Yamaguchi, M., & Kempermann, G. (2003) · Journal of Comparative Neurology · doi:10.1002/cne.10945 · Cited by 640 · see citing works
Notch signaling in the mammalian central nervous system: insights from mouse mutants
Yoon, K., & Gaiano, N. (2005) · Nature Neuroscience · doi:10.1038/nn1475 · Cited by 587 · see citing works
Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh
Favaro, R., Valotta, M., Ferri, L., Latorre, E., Mariani, J., Giachino, C., Lancini, C., Tosetti, V., Ottolenghi, S., Taylor, V., et al. (2009) · Nature Neuroscience · doi:10.1038/nn.2397 · Cited by 504 · see citing works
Dynamic Contribution of Nestin-Expressing Stem Cells to Adult Neurogenesis
Lagace, D. C., Whitman, M. C., Noonan, M. A., Ables, J. L., DeCarolis, N. A., Arguello, A. A., Donovan, M. H., Fischer, S. J., Farnbauch, L. A., Beech, R. D., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3812-07.2007 · Cited by 502 · see citing works
Self-citationGeling, A., Steiner, H., Willem, M., Bally‐Cuif, L., & Haass, C. (2002) · The EMBO Reports · doi:10.1093/embo-reports/kvf124 · Cited by 497 · cited 1× · see citing works
“Activation of Notch1 requires gammasecretase cleavage, therefore GSI also inhibit Notch1 activity (Geling et al., 2002) and SGZ progenitor proliferation (Breunig et al., 2007).”
BackgroundForebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke
Carlén, M., Meletis, K., Göritz, C., Darsalia, V., Evergren, E., Tanigaki, K., Amendola, M., Barnabé‐Heider, F., Yeung, M. S. Y., Naldini, L., et al. (2009) · Nature Neuroscience · doi:10.1038/nn.2268 · Cited by 453 · see citing works
Isolation and culture of adult neurons and neurospheres
Brewer, G. J., & Torricelli, J. R. (2007) · Nature Protocols · doi:10.1038/nprot.2007.207 · Cited by 448 · see citing works
Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus
Breunig, J. J., Silbereis, J. C., Vaccarino, F. M., Šestan, N., & RAKIC, P. T. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710156104 · Cited by 402 · see citing works
Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease
Donovan, M. H., Yazdani, U., Norris, R. D., Games, D., German, D. C., & Eisch, A. J. (2006) · The Journal of Comparative Neurology · doi:10.1002/cne.20840 · Cited by 350 · see citing works
Self-citationNeurogenesis and Alzheimer's disease: At the crossroads
Lazarov, O., & Marr, R. A. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.08.009 · Cited by 326 · see citing works
Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance
Lagace, D. C., Donovan, M. H., DeCarolis, N. A., Farnbauch, L. A., Malhotra, S., Berton, O., Nestler, E. J., Krishnan, V., & Eisch, A. J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910072107 · Cited by 314 · see citing works
Self-citationDevelopment of neural stem cell in the adult brain
Duan, X., Kang, E., Liu, C. Y., Ming, G., & Song, H. (2008) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2008.04.001 · Cited by 302 · see citing works
Physical Activity and the Regulation of Neurogenesis in the Adult and Aging Brain
Fabel, K. S., & Kempermann, G. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8031-4 · Cited by 265 · see citing works
Crossing paths with Notch in the hyper-network
Hurlbut, G. D., Kankel, M. W., Lake, R. J., & Artavanis‐Tsakonas, S. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.02.012 · Cited by 250 · see citing works
Adult Neurogenesis, Mental Health, and Mental Illness: Hope or Hype?: Figure 1.
Eisch, A. J., Cameron, H. A., Encinas, J. M., Meltzer, L. A., Ming, G., & Overstreet‐Wadiche, L. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3798-08.2008 · Cited by 247 · see citing works
Self-citationYoung and excitable: the function of new neurons in the adult mammalian brain
Doetsch, F. K., & Hen, R. (2005) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2005.01.018 · Cited by 236 · see citing works
The antidepressant effect of running is associated with increased hippocampal cell proliferation
Bjørnebekk, A., Mathé, A. A., & Brené, S. (2005) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145705005122 · Cited by 231 · see citing works
Temporal regulation of Cre recombinase activity in neural stem cells
Imayoshi, I., Ohtsuka, T., METZGER, D., Chambon, P., & Kageyama, R. (2006) · genesis · doi:10.1002/dvg.20212 · Cited by 207 · see citing works
Natural variation and genetic covariance in adult hippocampal neurogenesis
Kempermann, G., Chesler, E. J., Lu, L., Williams, R. W., & Gage, F. H. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510291103 · Cited by 205 · see citing works
Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain
Naylor, A. S., Bull, C., Nilsson, M. K. L., Zhu, C., Björk‐Eriksson, T., Eriksson, P. S., Blomgren, K., & Kuhn, H. G. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711128105 · Cited by 205 · see citing works
Steiner, B., Zurborg, S., Hörster, H., Fabel, K., & Kempermann, G. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.04.023 · Cited by 165 · see citing works
Regulation of neural progenitor cell development in the nervous system
Corbin, J. G., Gaiano, N., Juliano, S. L., Poluch, S., Stancik, E. K., & Haydar, T. F. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05522.x · Cited by 145 · see citing works
Kitamura, T., Mishina, M., & Sugiyama, H. (2003) · Neuroscience Research · doi:10.1016/s0168-0102(03)00171-8 · Cited by 134 · see citing works
Hill, M. N., Titterness, A. K., Morrish, A. C., Carrier, E. J., Lee, T. T. ‐., Gil‐Mohapel, J., Gorzalka, B. B., Hillard, C. J., & Christie, B. R. (2009) · Hippocampus · doi:10.1002/hipo.20647 · Cited by 129 · see citing works
Wang, X., Mao, X., Xie, L., Greenberg, D. A., & Jin, K. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.83 · Cited by 127 · see citing works
Cdk5 is essential for adult hippocampal neurogenesis
Lagace, D. C., Benavides, D. R., Kansy, J. W., Mapelli, M., Greengard, P., Bibb, J. A., & Eisch, A. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810137105 · Cited by 119 · see citing works
Self-citationMandyam, C. D., Norris, R. D., & Eisch, A. J. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20090 · Cited by 116 · see citing works
Self-citationNotch activity in the nervous system: to switch or not switch?
Cau, E., & Blader, P. (2009) · Neural Development · doi:10.1186/1749-8104-4-36 · Cited by 109 · see citing works
The impact of voluntary exercise on mental health in rodents: A neuroplasticity perspective
Pietropaolo, S., Sun, Y., Li, R., Brana, C., Feldon, J., & Yee, B. K. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.03.014 · Cited by 99 · see citing works
Donovan, M. H., Yamaguchi, M., & Eisch, A. J. (2008) · Hippocampus · doi:10.1002/hipo.20410 · Cited by 95 · see citing works
Self-citationExercise‐induced promotion of hippocampal cell proliferation requires β‐endorphin
Koehl, M., Meerlo, P., Gonzales, D., Rontal, A., Turek, F. W., & Abrous, D. N. (2008) · The FASEB Journal · doi:10.1096/fj.07-099101 · Cited by 95 · see citing works
Notch controls proliferation and differentiation of stem cells in a dose‐dependent manner
Guentchev, M., & McKay, R. D. G. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.04766.x · Cited by 86 · see citing works
Guo, D., Ye, J., Dai, J., Li, L.-Z., Chen, F., Ma, D., & Ji, C. (2008) · Leukemia Research · doi:10.1016/j.leukres.2008.10.026 · Cited by 86 · see citing works
Lafenêtre, P. (2009) · Frontiers in Behavioral Neuroscience · doi:10.3389/neuro.08.034.2009 · Cited by 80 · see citing works
Bednarczyk, M. R., Aumont, A., Décary, S., Bergeron, R., & Fernandes, K. J. L. (2009) · Hippocampus · doi:10.1002/hipo.20621 · Cited by 79 · see citing works
Annenkov, A. E. (2009) · Molecular Neurobiology · doi:10.1007/s12035-009-8081-0 · Cited by 73 · see citing works
Modulating Notch signaling by pathway-intrinsic and pathway-extrinsic mechanisms
Poellinger, L., & Lendahl, U. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2008.07.013 · Cited by 67 · see citing works
Cell-intrinsic signals that regulate adult neurogenesis in vivo: insights from inducible approaches
Johnson, M. A., Ables, J. L., & Eisch, A. J. (2009) · BMB Reports · doi:10.5483/bmbrep.2009.42.5.245 · Cited by 65 · see citing works
Self-citationStem cells of the adult mammalian brain and their niche
Başak, O., & Taylor, V. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8544-x · Cited by 57 · see citing works
Radtke, F., Schweisguth, F., & Pear, W. S. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400585 · Cited by 56 · see citing works
Self-citationDahlhaus, M., Hermans, J. M., Woerden, L. H. V., Saiepour, M. H., Nakazawa, K., Mansvelder, H. D., Heimel, J. A., & Levelt, C. N. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1348-08.2008 · Cited by 41 · see citing works
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Neurogenesis in the embryonic and adult brain: same regulators, different roles
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- Authors
- Ables, J. L., DeCarolis, N. A., Johnson, M. A., Rivera, P. D., Gao, Z., Cooper, D. C., Radtke, F., Hsieh, J., & Eisch, A. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Colorado Boulder (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-08-04
- Volume
- 30
- Issue
- 31
- Pages
- 10484-10492
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2935844
- OpenAlex
- W2059201000
- Cited by
- 292
- References
- 55
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 20 · 2020: 13 · 2019: 21 · 2018: 20 · 2017: 25 · 2016: 15 · 2015: 19 · 2014: 28 · 2013: 27 · 2012: 26
- FWCI
- 8.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (NIH T32, DA007290)
- National Institute of Mental Health (MH076690, T32MH076690)
- National Institute on Drug Abuse (DA023701, R21DA023701, DA023555, K02DA023555, DA016765, T32DA007290, K01DA017750, R01DA016765)
- National Institute of Neurological Disorders and Stroke (F31NS064632)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Notch1 signaling, adult hippocampal neurogenesis, neural stem cells, subgranular zone, dentate gyrus granule cells, running, compensatory neurogenesis, neurogenic niche
- MeSH terms
- Animals, Cell Count, Hippocampus, Immunohistochemistry, Mice, Transgenic, Neurons, Physical Conditioning, Animal, Mice, Receptor, Notch1, Adult Stem Cells, Neurogenesis
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