Area-specific regulation of quiescent neural stem cells by Notch3 in the adult mouse subependymal zone
Open accessAbstract
In the adult mammalian brain, neural stem cells (NSCs) generate new neurons throughout the mammal's lifetime. The balance between quiescence and active cell division among NSCs is crucial in producing appropriate numbers of neurons while maintaining the stem cell pool for a long period. The Notch signaling pathway plays a central role in both maintaining quiescent NSCs (qNSCs) and promoting cell division of active NSCs (aNSCs), although no one knows how this pathway regulates these apparently opposite functions. Notch1 has been shown to promote proliferation of aNSCs without affecting qNSCs in the adult mouse subependymal zone (SEZ). In this study, we found that Notch3 is expressed to a higher extent in qNSCs than in aNSCs while Notch1 is preferentially expressed in aNSCs and transit-amplifying progenitors in the adult mouse SEZ. Furthermore, Notch3 is selectively expressed in the lateral and ventral walls of the SEZ. Knockdown of Notch3 in the lateral wall of the adult SEZ increased the division of NSCs. Moreover, deletion of theNotch3gene resulted in significant reduction of qNSCs specifically in the lateral and ventral walls, compared with the medial and dorsal walls, of the lateral ventricles. Notch3 deletion also reduced the number of qNSCs activated after antimitotic cytosine β-D-arabinofuranoside (Ara-C) treatment. Importantly, Notch3 deletion preferentially reduced specific subtypes of newborn neurons in the olfactory bulb derived from the lateral walls of the SEZ. These results indicate that Notch isoforms differentially control the quiescent and proliferative steps of adult SEZ NSCs in a domain-specific manner. SIGNIFICANCE STATEMENTIn the adult mammalian brain, the subependymal zone (SEZ) of the lateral ventricles is the largest neurogenic niche, where neural stem cells (NSCs) generate neurons. In this study, we found that Notch3 plays an important role in the maintenance of quiescent NSCs (qNSCs), while Notch1 has been reported to act as a regulator of actively cycling NSCs. Furthermore, we found that Notch3 is specifically expressed in qNSCs located in the lateral and ventral walls of the lateral ventricles and regulates neuronal production of NSCs in a region-specific manner. Our results indicate that Notch3, by maintaining the quiescence of a subpopulation of NSCs, confers a region-specific heterogeneity among NSCs in the adult SEZ.
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Fgfr and Notch signaling and oxidative phosphorylation showed lateral wall and male enrichment.
“Several molecular and metabolic processes important for stem cell self-renewal, maintenance, and proliferation, such as Fgfr and Notch signaling and oxidative phosphorylation, showed lateral wall and male enrichment (Engler et al., 2018; Kawai et al., 2017; Llorens-Bobadilla et al., 2015; Zheng et al., 2004).”
From Single-Cell Analysis of Regional Differences in Adult V-SVZ Neural Stem Cell Lineages (2019) · cites this paper as Kawai et al., 2017
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Hsp83/Hsp90 Physically Associates with Insulin Receptor to Promote Neural Stem Cell Reactivation
Huang, J., & Wang, H. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.08.014 · Cited by 30 · see citing works
“Interestingly, these quiescentNSCs can be reactivated and participate in neurogenesis upon various extrinsic stimuli (Ahn and Joyner, 2005; Daynac et al., 2013, 2016; Faiz et al., 2015; Kawai et al., 2017; Lugert et al., 2010;Wang et al., 2011).”
BackgroundLysosomes and signaling pathways for maintenance of quiescence in adult neural stem cells
Kobayashi, T., & Kageyama, R. (2021) · The FEBS Journal · doi:10.1111/febs.15555 · Cited by 28 · see citing works
Autotherapies: Enhancing Endogenous Healing and Regeneration
Lumelsky, N. L., O’Hayre, M., Chander, P., Shum, L., & Somerman, M. J. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.08.004 · Cited by 28 · see citing works
Dray, N., Than‐Trong, E., & Bally‐Cuif, L. (2020) · BioEssays · doi:10.1002/bies.202000228 · Cited by 26 · see citing works
Regulation of Cell Cycle Entry and Exit: A Single Cell Perspective
Coller, H. A. (2019) · Comprehensive physiology · doi:10.1002/cphy.c190014 · Cited by 30 · see citing works
Coolen, M., Labusch, M., Mannioui, A., Hoppe, B., Baumgart, M., & Bally‐Cuif, L. (2020) · Current Biology · doi:10.1016/j.cub.2019.12.046 · Cited by 25 · see citing works
A novel stem cell type at the basal side of the subventricular zone maintains adult neurogenesis
Baur, K., Abdullah, Y., Mandl, C., Hölzl‐Wenig, G., Shi, Y., Schmidt-Edelkraut, U., Khatri, P. R., Hagenston, A. M., Irmler, M., Beckers, J., et al. (2022) · EMBO Reports · doi:10.15252/embr.202154078 · Cited by 22 · see citing works
“It is well established that Notch signalling is essential to maintain stemness during quiescence of NSCs and ependymal cell differentiation (Carlen et al , 2009; Imayoshi et al , 2010; Kawaguchi et al , 2013; Kawai et al , 2017; Engler et al , 2018; Than-Trong et al , 2018).”
Neural stem cell heterogeneity in the mammalian forebrain
Adams, K. V., & Morshead, C. M. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.06.005 · Cited by 23 · see citing works
“Notch activity, which is mediated by expression of Sox2 and SHH, has been shown to maintain NPCs in an undifferentiated state (Louvi and Artavanis-Tsakonas, 2006; Kong et al., 2015; Kawai et al., 2017).”
Histone lysine methyltransferase Pr-set7/SETD8 promotes neural stem cell reactivation
Huang, J., Gujar, M. R., Deng, Q., Chia, S. Y., Li, S., Tan, P. B. O., Sung, W.-K. K., & Wang, H. (2021) · EMBO Reports · doi:10.15252/embr.202050994 · Cited by 23 · see citing works
“…response to various physiological stimuli, such as injury, the presence of nutrients, and physical exercise (Ahn & Joyner, 2005; Lugert et al , 2010; Wang et al , 2011; Daynac et al , 2013; Faiz et al , 2015; Daynac et al , 2016; Kawai et al , 2017; Otsuki & Brand, 2017, 2020; Ding et al , 2020).”
Quiescent Adult Neural Stem Cells: Developmental Origin and Regulatory Mechanisms
Meng, H., Yu, H., Zhang, K., Yi, X., Meng, X., Kang, E., Wu, S., Deng, W., & Wang, Y. (2024) · Neuroscience Bulletin · doi:10.1007/s12264-024-01206-1 · Cited by 21 · see citing works
“In contrast to Notch1 and Notch2, Notch3 signaling participates in maintaining both the stemness and quiescence of adult NSCs [35].”
BackgroundNotch signaling in neurogenesis
McLaren, M. E., & Butts, J. C. (2025) · Development · doi:10.1242/dev.204589 · Cited by 18 · see citing works
Apical size and deltaA expression predict adult neural stem cell decisions along lineage progression
Mancini, L., Guirao, B., Ortica, S., Labusch, M., Cheysson, F., Bonnet, V., Phan, M.-S., Herbert, S., Mahou, P., Menant, E., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg7519 · Cited by 21 · see citing works
“The latter hypothesis is supported below. deltaA expression correlates with cell type, state, and quantitative apical parameters Notch signaling promotes quiescence and progenitor state maintenance in adult NSCs in zebrafish and mouse ( 7 , 30 , 38 – 40 ).”
Ehret, F., Traspas, R. M., Neumuth, M.-T., Hamann, B., Lasse, D., & Kempermann, G. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.617733 · Cited by 18 · see citing works
Distinctive properties of the interactions between Notch and Notch ligands
Hozumi, K. (2019) · Development Growth & Differentiation · doi:10.1111/dgd.12641 · Cited by 18 · see citing works
Neural Stem Cell Regulation in Zebrafish
Foley, T., Thétiot, M., & Bally‐Cuif, L. (2024) · Annual Review of Genetics · doi:10.1146/annurev-genet-111523-101949 · Cited by 18 · see citing works
Luque-Molina, I., Shi, Y., Abdullah, Y., Monaco, S., Hölzl‐Wenig, G., Mandl, C., & Ciccolini, F. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.05.004 · Cited by 15 · see citing works
“, 2012), leads to a decrease in the number of quiescent NSCs, especially in the lateral and ventral areas of the SEZ (Kawai et al., 2017).”
BackgroundOne progenitor to generate them all: new evidence for multi-fated neural progenitors
Álvarez, G., & Spassky, N. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.10.013 · Cited by 15 · see citing works
Wang, T., Han, Q., Lv, S., Zhang, L.-P., Li, H., Liu, J., Kuang, J., Sun, B., & Sun, J. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1592297 · Cited by 15 · see citing works
Ilie, O., Duta, R., Balmuș, I.-M., Săvucă, A., Petrovici, A., Nita, I.-B., Antoci, L.-M., Jijie, R., Mihai, C. T., Ciobica, A. S., et al. (2022) · Antioxidants · doi:10.3390/antiox11102040 · Cited by 13 · see citing works
Bao, Y., Chen, H., Cai, Z., Zheng, J., Zou, J., Shi, Y., & Jiang, L. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.03.001 · Cited by 11 · see citing works
Hes1 oscillation frequency correlates with activation of neural stem cells
Kaise, T., & Kageyama, R. (2021) · Gene Expression Patterns · doi:10.1016/j.gep.2021.119170 · Cited by 11 · see citing works
Zhang, Z., Su, Z., Li, Z., Li, J., Yu, W., Ye, G., Lin, J., Che, Y., Xu, P., Zeng, Y., et al. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.01.009 · Cited by 9 · see citing works
Identifying the Unique Role of Notch3 in Adult Neural Stem Cell Maintenance
Rieskamp, J. D., Denninger, J. K., & Dause, T. J. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.3531-17.2018 · Cited by 9 · see citing works
“While Kawai et al. (2017) did not explore spatial expression patterns of Notch1 and Notch2, another Notch paralog shown to be expressed in the SEZ (Basak et al., 2012), it is tempting to speculate that these Notch receptors also exhibit spatially restricted expression which could explain the…”
BackgroundInfluentialTIMP3 promotes the maintenance of neural stem-progenitor cells in the mouse subventricular zone
Fang, L., Kuniya, T., Harada, Y., Yasuda, O., Maeda, N., Suzuki, Y., Kawaguchi, D., & Gotoh, Y. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1149603 · Cited by 8 · see citing works
“Notch3 has been shown to be responsible for the maintenance of quiescent adult NSCs (Kawai et al., 2017; Than-trong et al., 2018).”
BackgroundMethodEmbracing the heterogeneity of neural stem cells in the subventricular zone
Apostolou, S., & Donega, V. (2025) · Stem Cell Reports · doi:10.1016/j.stemcr.2025.102452 · Cited by 6 · see citing works
The Critical Balance Between Quiescence and Reactivation of Neural Stem Cells
Elkin, A. M., Robbins, S., Barros, C. S., & Bossing, T. (2025) · Biomolecules · doi:10.3390/biom15050672 · Cited by 6 · see citing works
“Loss of Notch effector genes Hes1 and Hes5 or deletion of downstream mediator Rbpj results in activation and premature differentiation of NSCs and depletion of the NSC pool in the CNS of adult mice [5,82–84].”
InfluentialVerkerke, M., Werkman, M. H., & Donega, V. (2025) · Stem Cell Reports · doi:10.1016/j.stemcr.2025.102533 · Cited by 5 · see citing works
Drugs and Endogenous Factors as Protagonists in Neurogenic Stimulation
Chiareli, R. A., Marques, B. L., Carvalho, G. A., Souza, R. T. V., Santana, P. H. G., Santiago, H. C., Pinto, M. C. X., Birbrair, A., Parreira, R. C., Ulrich, H., et al. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10423-y · Cited by 5 · see citing works
Notch3 is an asymmetric gene and a modifier of heart looping defects in Nodal mouse mutants
Bønnelykke, T. H., Chabry, M.-A., Perthame, É., Dombrowsky, G., Berger, F. F., Dittrich, S., Hitz, M., Desgrange, A., & Meilhac, S. M. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3002598 · Cited by 5 · see citing works
Regulation of Cell Cycle Entry and Exit: A Single Cell Perspective
Coller, H. A. (2020) · Comprehensive physiology · doi:10.1002/j.2040-4603.2020.tb00110.x · Cited by 5 · see citing works
Chang, C., Bai, W., Li, J., Huo, S., Wang, T., & Shao, J. (2023) · Current Therapeutic Research · doi:10.1016/j.curtheres.2023.100691 · Cited by 4 · see citing works
Aging of the ventricular-subventricular zone neural stem cell niche
Merson, T. D. (2020) · Advances in stem cells and their niches · doi:10.1016/bs.asn.2020.07.001 · Cited by 4 · see citing works
Parmigiani, E., & Giachino, C. (2022) · Cancers · doi:10.3390/cancers14215409 · Cited by 3 · see citing works
“Intriguingly, data suggest that transformed NSCs can outcompete neighboring NSCs by repressing their proliferation through Notch signaling [57].”
InfluentialGenerating neurons in the embryonic and adult brain: compared principles and mechanisms
Chouly, M., & Bally‐Cuif, L. (2024) · Comptes Rendus Biologies · doi:10.5802/crbiol.167 · Cited by 3 · see citing works
Sox5 controls the establishment of quiescence in neural stem cells during postnatal development
Medina-Menéndez, C., 李灵玲, Tirado-Melendro, P., Rodríguez‐Martín, P., Melgarejo, E., Díaz-García, M., Valdés-Bescós, M., Segundo, R. L.-S., & Morales, A. V. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3002654 · Cited by 3 · see citing works
“These include BMP4 [14,15] and its downstream effectors Id1 and Id4 [16–18]; TGF β [19]; Delta/Notch pathway [20–22] and the MFGE8/integrin/ILK pathway [23], amongst others.”
Ortica, S., Herrera, M. M., Degroux, L., Rochette, B., Dray, N., & Bally‐Cuif, L. (2026) · Nature Communications · doi:10.1038/s41467-026-70478-0 · Cited by 4 · see citing works
“…and 3 are strongly expressed in quiescent NSCs and promote quiescence: upon lowering Notch3 activity in zebra fi sh, quiescent pallial NSCs enter proliferation 24 ; like-wise, abrogation of Notch2 and Notch3 also leads to NSC quiescence exit and proliferation in the mouse SEZ and SGZ 20 – 22 .”
Heterogeneity of Neural Stem Cells in the Ventricular–Subventricular Zone
Rushing, G. V., Bollig, M. K., & Ihrie, R. A. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-24108-7_1 · Cited by 3 · see citing works
The cellular Notch1 protein promotes KSHV reactivation in an Rta-dependent manner
DeCotiis, J., Han, S. M., Mello, H. F., Goyeneche, C., Tovar, G. M., Jin, L., Bellofatto, V., & Lukac, D. M. (2024) · Journal of Virology · doi:10.1128/jvi.00788-24 · Cited by 2 · see citing works
Yakovleva, S. A., Knyazeva, A., Yunusova, A., Allayarova, E. R., Lanshakov, D. A., Malashicheva, A., & Шнайдер, Т. А. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157309 · Cited by 3 · see citing works
“Previous studies have shown that murine Notch receptors regulate neuronal cell proliferation [46,56–59].”
Human endothelial cells promote a human neural stem cell type B phenotype via Notch signaling
Gutierrez, B., Liu, T. C., Rodriguez, C., Pastor-Alonso, O., Lambing, H., Paredes, M. F., & Flanagan, L. A. (2025) · Nature Communications · doi:10.1038/s41467-025-60194-6 · Cited by 3 · see citing works
“The Notch pathway is known to promote quiescence and maintenance of NSPCs in the embryonic and adult mouse brain 35,78 – 80 .”
Resident Neural Stem Cell Niches and Regeneration: The Splendors and Miseries of Adult Neurogenesis
Baklaushev, V. P., Yusubalieva, G. M., Samoilova, E. M., & Викторович, Б. В. (2022) · Russian Journal of Developmental Biology · doi:10.1134/s1062360422030080 · Cited by 1 · see citing works
Thétiot, M., Sart, S., Cussigh, D., Coolen, M., Baroud, C. N., & Bally‐Cuif, L. (2025) · Biology of the Cell · doi:10.1111/boc.70007 · Cited by 2 · see citing works
“As major quiescent pathways include Notch signaling (Alunni et al. 2013; Dray et al. 2021; Kawai et al. 2017), we hypothesized that cell–cell contact interactions, permitted in a 3D set-up, might favor the induction of a quiescence state.”
Neural stem cells-from quiescence to differentiation and potential clinical uses
Dobranici, A., Dinescu, S., & Costache, M. (2021) · Reviews in Biological and Biomedical Sciences · doi:10.31178/rbbs.2021.4.1.2
Role of Yap1 in adult neural stem cell activationPreprint
Fan, W., Jurado‐Arjona, J., Alanis‐Lobato, G., Péron, S., Berger, C., Andrade-Navarro, M. A., Falk, S., & Berninger, B. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.12.475985
“…in the bidirectional traffic between quiescence and activation, including BMP (Mira et al., 2010), Notch (Engler et al., 2018, Harada et al., 2021, Kawai et al., 2017, Zhang et al., 2019), VEGFR3 (Han et al., 2015) and Wnt signaling (Lie et al., 2005, Wexler et al., 2009), but also include…”
BackgroundNotch3 is a genetic modifier of NODAL signalling for patterning asymmetry during mouse heart loopingPreprint
Bønnelykke, T. H., Chabry, M.-A., Perthame, É., Desgrange, A., & Meilhac, S. M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.25.586543
Kempermann, G. (2025) · Oxford University Press eBooks · doi:10.1093/med/9780197519233.003.0009
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“The telencephalon remains, without a doubt, the most investigated brain region, as it shares many features and homologues with the mammalian telencephalon, especially when considering adult neurogenesis [63–66].”
Li, J., Ju, F., Huang, Z., Yu, L., Qin, J., Yang, Y., Sun, W., Ji, Y., Zhao, C., & Yuan, H. M. (2026) · Developmental Neurobiology · doi:10.1002/dneu.70013
“Notch receptors play different roles in regulating NSC activation in the adult mammalian CNS (Basak et al. 2012 , Engler et al. 2018 , Kawai et al. 2017 ).”
Spatiotemporal control of Neural Stem Cell decisions in the adult zebrafish telencephalon
Mancini, L. (2020) · theses.fr (ABES) · doi:10.70675/0693891fz9d70z4939zb562zc001317d88eb
Unraveling the role of the lysosomal protein Prosaposin in neural stem cell quiescence
Labusch, M. (2022) · theses.fr (ABES) · doi:10.70675/87ff1a05z0defz40caza788z86260ae829ce
Lampada, A., Rolando, C., Whittle, N., Engler, A., Tillmann, J. F., Freire, J. A., Giachino, C., Parmigiani, E., Saotome, I., Louvi, A., et al. (2026) · Science Advances · doi:10.1126/sciadv.aed3625
- Authors
- Kawai, H., Kawaguchi, D., Kuebrich, B. D., Kitamoto, T., Yamaguchi, M., Gotoh, Y., & Furutachi, S.
- Affiliations
- The University of Tokyo (JP)
- Kitasato University (JP)
- Kōchi University (JP)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-11-03
- Volume
- 37
- Issue
- 49
- Pages
- 11867-11880
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6596834
- OpenAlex
- W2765266240
- Cited by
- 85
- References
- 51
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 12 · 2020: 17 · 2019: 11 · 2018: 8
- FWCI
- 4.17
- 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)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (10011, JP16H06481, 15H05773)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- Notch3, Notch1, neural stem cells, quiescent neural stem cells, subventricular zone, adult neurogenesis, Notch signaling, lateral ventricle, olfactory bulb, cytarabine, stem cell quiescence, lateral wall, neurogenic niche
- MeSH terms
- Receptor, Notch3, Age Factors, Animals, Cells, Cultured, Mice, Inbred C57BL, Mice, Knockout, Lateral Ventricles, Mice, Adult Stem Cells, Neural Stem Cells
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