Waking up quiescent neural stem cells: Molecular mechanisms and implications in neurodevelopmental disorders

1. Wang Y-Z, Plane JM, Jiang P, Zhou CJ, Deng W. Concise Review: Quiescent and Active States of Endogenous Adult Neural Stem Cells: Identification and Characterization. STEM CELLS. 2011;29(6):907–12. doi: 10.1002/stem.644 21557389

2. Fabel K, Kempermann G. Physical activity and the regulation of neurogenesis in the adult and aging brain. Neuromolecular Med. 2008;10(2):59–66. doi: 10.1007/s12017-008-8031-4 18286387.

3. Lucassen PJ, Meerlo P, Naylor AS, van Dam AM, Dayer AG, Fuchs E, et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action. Eur Neuropsychopharmacol. 2010;20(1):1–17. Epub 2009 Sept 11. doi: 10.1016/j.euroneuro.2009.08.003 19748235.

4. Lee SW, Clemenson GD, Gage FH. New neurons in an aged brain. Behav Brain Res. 2012;227(2):497–507. Epub 2011 Oct 18. doi: 10.1016/j.bbr.2011.10.009 22024433; PubMed Central PMCID: PMC3264739.

5. Doetsch F, Caillé I, Lim DA, García-Verdugo JM, Alvarez-Buylla A. Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain. Cell. 1999;97(6):703–16. doi: 10.1016/s0092-8674(00)80783-7 10380923.

6. Seri B, García-Verdugo JM, McEwen BS, Alvarez-Buylla A. Astrocytes Give Rise to New Neurons in the Adult Mammalian Hippocampus. Journal of Neuroscience. 2001;21(18):7153–60. doi: 10.1523/JNEUROSCI.21-18-07153.2001 11549726.

7. Hartenstein V, Rudloff E, Campos-Ortega JA. The pattern of proliferation of the neuroblasts in the wild-type embryo of Drosophila melanogaster. Roux's archives of developmental biology: the official organ of the EDBO. 1987;196(8):473–85. doi: 10.1007/BF00399871 28305704.

8. Truman JW, Bate M. Spatial and temporal patterns of neurogenesis in the central nervous system of Drosophila melanogaster. Dev Biol. 1988;125(1):145–57. doi: 10.1016/0012-1606(88)90067-x 3119399.

9. Ito K, Hotta Y. Proliferation pattern of postembryonic neuroblasts in the brain of Drosophila melanogaster. Developmental Biology. 1992;149(1):134–48. doi: 10.1016/0012-1606(92)90270-q 1728583

10. Prokop A, Bray S, Harrison E, Technau GM. Homeotic regulation of segment-specific differences in neuroblast numbers and proliferation in the Drosophila central nervous system. Mechanisms of development. 1998;74(1–2):99–110. doi: 10.1016/s0925-4773(98)00068-9 9651493.

11. White K, Grether ME, Abrams JM, Young L, Farrell K, Steller H. Genetic control of programmed cell death in Drosophila. Science. 1994;264(5159):677–83. doi: 10.1126/science.8171319 8171319.

12. Tsuji T, Hasegawa E, Isshiki T. Neuroblast entry into quiescence is regulated intrinsically by the combined action of spatial Hox proteins and temporal identity factors. Development. 2008;135(23):3859–69. doi: 10.1242/dev.025189 18948419.

13. Homem CC, Knoblich JA. Drosophila neuroblasts: a model for stem cell biology. Development. 2012;139(23):4297–310. doi: 10.1242/dev.080515 23132240.

14. Britton JS, Edgar Ba. Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms. Development (Cambridge, England). 1998;125(11):2149–58. 9570778

15. Chell JM, Brand AH. Nutrition-Responsive Glia Control Exit of Neural Stem Cells from Quiescence. Cell. 2010;143(7):1161–73. doi: 10.1016/j.cell.2010.12.007 21183078; PubMed Central PMCID: PMC3087489.

16. Colombani J, Raisin S, Pantalacci S, Radimerski T, Montagne J, Leopold P. A nutrient sensor mechanism controls Drosophila growth. Cell. 2003;114(6):739–49. doi: 10.1016/s0092-8674(03)00713-x 14505573.

17. Geminard C, Rulifson EJ, Leopold P. Remote control of insulin secretion by fat cells in Drosophila. Cell Metab. 2009;10(3):199–207. doi: 10.1016/j.cmet.2009.08.002 19723496.

18. Sousa-Nunes R, Yee LL, Gould AP. Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila. Nature. 2011;471(7339):508–12. doi: 10.1038/nature09867 21346761; PubMed Central PMCID: PMC3146047.

19. Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7(1):a020412. doi: 10.1101/cshperspect.a020412 25561720; PubMed Central PMCID: PMC4292164.

20. Reese TS, Karnovsky MJ. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol. 1967;34(1):207–17. doi: 10.1083/jcb.34.1.207 6033532; PubMed Central PMCID: PMC2107213.

21. O'Brown NM, Pfau SJ, Gu C. Bridging barriers: a comparative look at the blood-brain barrier across organisms. Genes Dev. 2018;32(7–8):466–78. doi: 10.1101/gad.309823.117 29692355; PubMed Central PMCID: PMC5959231.

22. De Bock M, Wang N, Decrock E, Bol M, Gadicherla AK, Culot M, et al. Endothelial calcium dynamics, connexin channels and blood-brain barrier function. Prog Neurobiol. 2013;108:1–20. doi: 10.1016/j.pneurobio.2013.06.001 23851106.

23. Campos-Bedolla P, Walter FR, Veszelka S, Deli MA. Role of the blood-brain barrier in the nutrition of the central nervous system. Arch Med Res. 2014;45(8):610–38. doi: 10.1016/j.arcmed.2014.11.018 25481827.

24. Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature. 2014;509(7501):503–6. doi: 10.1038/nature13241 24828044.

25. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7(1):41–53. doi: 10.1038/nrn1824 16371949.

26. Guemez-Gamboa A, Nguyen LN, Yang H, Zaki MS, Kara M, Ben-Omran T, et al. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat Genet. 2015;47(7):809–13. doi: 10.1038/ng.3311 26005868; PubMed Central PMCID: PMC4547531.

27. Alakbarzade V, Hameed A, Quek DQ, Chioza BA, Baple EL, Cazenave-Gassiot A, et al. A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Nat Genet. 2015;47(7):814–7. doi: 10.1038/ng.3313 26005865.

28. Gómez-Gaviro MV, Scott CE, Sesay AK, Matheu A, Booth S, Galichet C, et al. Betacellulin promotes cell proliferation in the neural stem cell niche and stimulates neurogenesis. Proceedings of the National Academy of Sciences. 2012;109(4):1317–22. doi: 10.1073/pnas.1016199109 22232668; PubMed Central PMCID: PMC3268286.

29. Delgado AC, Ferrón SR, Vicente D, Porlan E, Perez-Villalba A, Trujillo CM, et al. Endothelial NT-3 Delivered by Vasculature and CSF Promotes Quiescence of Subependymal Neural Stem Cells through Nitric Oxide Induction. Neuron. 2014;83(3):572–85. doi: 10.1016/j.neuron.2014.06.015 25043422

30. Carreira BP, Morte MI, Inácio Â, Costa G, Rosmaninho-Salgado J, Agasse F, et al. Nitric Oxide Stimulates the Proliferation of Neural Stem Cells Bypassing the Epidermal Growth Factor Receptor. Stem Cells. 2010;28(7):1219–30. doi: 10.1002/stem.444 20506358

31. Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344(6184):630–4. doi: 10.1126/science.1251141 24797482

32. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90–4. doi: 10.1038/nature10357 21886162

33. Smith LK, He Y, Park J-S, Bieri G, Snethlage CE, Lin K, et al. β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nature Medicine. 2015;21(8):932–7. doi: 10.1038/nm.3898 26147761

34. Shingo T, Gregg C, Enwere E, Fujikawa H, Hassam R, Geary C, et al. Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science. 2003;299(5603):117–20. doi: 10.1126/science.1076647 12511652.

35. Shingo T, Sorokan ST, Shimazaki T, Weiss S. Erythropoietin Regulates the In Vitro and In Vivo Production of Neuronal Progenitors by Mammalian Forebrain Neural Stem Cells. Journal of Neuroscience. 2001;21(24):9733–43. doi: 10.1523/JNEUROSCI.21-24-09733.2001 11739582.

36. Iadecola C. The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron. 2017;96(1):17–42. doi: 10.1016/j.neuron.2017.07.030 28957666; PubMed Central PMCID: PMC5657612.

37. Mayer F, Mayer N, Chinn L, Pinsonneault RL, Kroetz D, Bainton RJ. Evolutionary conservation of vertebrate blood-brain barrier chemoprotective mechanisms in Drosophila. J Neurosci. 2009;29(11):3538–50. doi: 10.1523/JNEUROSCI.5564-08.2009 19295159; PubMed Central PMCID: PMC3040577.

38. Banerjee S, Bhat MA. Neuron-glial interactions in blood-brain barrier formation. Annu Rev Neurosci. 2007;30:235–58. doi: 10.1146/annurev.neuro.30.051606.094345 17506642; PubMed Central PMCID: PMC2824917.

39. Stork T, Engelen D, Krudewig A, Silies M, Bainton RJ, Klambt C. Organization and function of the blood-brain barrier in Drosophila. J Neurosci. 2008;28(3):587–97. doi: 10.1523/JNEUROSCI.4367-07.2008 18199760.

40. Limmer S, Weiler A, Volkenhoff A, Babatz F, Klambt C. The Drosophila blood-brain barrier: development and function of a glial endothelium. Front Neurosci. 2014;8:365. doi: 10.3389/fnins.2014.00365 25452710; PubMed Central PMCID: PMC4231875.

41. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37(1):13–25. Epub 2009 Aug 5. doi: 10.1016/j.nbd.2009.07.030 19664713.

42. Freeman MR. Drosophila Central Nervous System Glia. Cold Spring Harb Perspect Biol. 2015;7(11):a020552. doi: 10.1101/cshperspect.a020552 25722465; PubMed Central PMCID: PMC4632667.

43. Underwood LE, Thissen JP, Lemozy S, Ketelslegers JM, Clemmons DR. Hormonal and nutritional regulation of IGF-I and its binding proteins. Horm Res. 1994;42(4–5):145–51. doi: 10.1159/000184187 7532613.

44. Brogiolo W, Stocker H, Ikeya T, Rintelen F, Fernandez R, Hafen E. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol. 2001;11(4):213–21. doi: 10.1016/s0960-9822(01)00068-9 11250149.

45. Garelli A, Gontijo AM, Miguela V, Caparros E, Dominguez M. Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation. Science. 2012;336(6081):579–82. doi: 10.1126/science.1216735 22556250.

46. Ikeya T, Galic M, Belawat P, Nairz K, Hafen E. Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila. Curr Biol. 2002;12(15):1293–300. doi: 10.1016/s0960-9822(02)01043-6 12176357.

47. Rulifson EJ, Kim SK, Nusse R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science. 2002;296(5570):1118–20. doi: 10.1126/science.1070058 12004130.

48. Britton JS, Edgar BA. Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms. Development. 1998;125(11):2149–58. 9570778.

49. Spéder P, Brand Andrea H. Gap Junction Proteins in the Blood-Brain Barrier Control Nutrient-Dependent Reactivation of Drosophila Neural Stem Cells. Developmental Cell. 2014;30(3):309–21. doi: 10.1016/j.devcel.2014.05.021 25065772

50. Kar R, Batra N, Riquelme MA, Jiang JX. Biological role of connexin intercellular channels and hemichannels. Arch Biochem Biophys. 2012;524(1):2–15. doi: 10.1016/j.abb.2012.03.008 22430362; PubMed Central PMCID: PMC3376239.

51. Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002;417(6884):39–44. doi: 10.1038/417039a 11986659.

52. Anderson MF, Aberg MA, Nilsson M, Eriksson PS. Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain research Developmental brain research. 2002;134(1–2):115–22. doi: 10.1016/s0165-3806(02)00277-8 11947942.

53. Plum L, Schubert M, Bruning JC. The role of insulin receptor signaling in the brain. Trends in endocrinology and metabolism: TEM. 2005;16(2):59–65. doi: 10.1016/j.tem.2005.01.008 15734146.

54. van Houten M, Posner BI, Kopriwa BM, Brawer JR. Insulin-binding sites in the rat brain: in vivo localization to the circumventricular organs by quantitative radioautography. Endocrinology. 1979;105(3):666–73. doi: 10.1210/endo-105-3-666 223829.

55. Joseph D'Ercole A, Ye P. Expanding the mind: insulin-like growth factor I and brain development. Endocrinology. 2008;149(12):5958–62. doi: 10.1210/en.2008-0920 18687773; PubMed Central PMCID: PMC2613055.

56. Drago J, Murphy M, Carroll SM, Harvey RP, Bartlett PF. Fibroblast growth factor-mediated proliferation of central nervous system precursors depends on endogenous production of insulin-like growth factor I. Proceedings of the National Academy of Sciences of the United States of America. 1991;88(6):2199–203. doi: 10.1073/pnas.88.6.2199 2006157; PubMed Central PMCID: PMC51197.

57. Popken GJ, Hodge RD, Ye P, Zhang J, Ng W, O'Kusky JR, et al. In vivo effects of insulin-like growth factor-I (IGF-I) on prenatal and early postnatal development of the central nervous system. Eur J Neurosci. 2004;19(8):2056–68. doi: 10.1111/j.0953-816X.2004.03320.x 15090033.

58. Bondy CA, Cheng CM. Signaling by insulin-like growth factor 1 in brain. European journal of pharmacology. 2004;490(1–3):25–31. doi: 10.1016/j.ejphar.2004.02.042 15094071.

59. Aberg MA, Aberg ND, Hedbacker H, Oscarsson J, Eriksson PS. Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2000;20(8):2896–903. doi: 10.1523/JNEUROSCI.20-08-02896.2000 10751442.

60. D'Ercole AJ, Ye P, O'Kusky JR. Mutant mouse models of insulin-like growth factor actions in the central nervous system. Neuropeptides. 2002;36(2–3):209–20. doi: 10.1054/npep.2002.0893 12359511.

61. Kim JY, Duan X, Liu CY, Jang MH, Guo JU, Pow-anpongkul N, et al. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron. 2009;63(6):761–73. doi: 10.1016/j.neuron.2009.08.008 19778506; PubMed Central PMCID: PMC3075620.

62. Ka M, Condorelli G, Woodgett JR, Kim WY. mTOR regulates brain morphogenesis by mediating GSK3 signaling. Development. 2014;141(21):4076–86. doi: 10.1242/dev.108282 25273085; PubMed Central PMCID: PMC4302893.

63. Renault VM, Rafalski VA, Morgan AA, Salih DA, Brett JO, Webb AE, et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell. 2009;5(5):527–39. doi: 10.1016/j.stem.2009.09.014 19896443; PubMed Central PMCID: PMC2775802.

64. Paik JH, Ding Z, Narurkar R, Ramkissoon S, Muller F, Kamoun WS, et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell. 2009;5(5):540–53. doi: 10.1016/j.stem.2009.09.013 19896444; PubMed Central PMCID: PMC3285492.

65. Aberg MA, Aberg ND, Palmer TD, Alborn AM, Carlsson-Skwirut C, Bang P, et al. IGF-I has a direct proliferative effect in adult hippocampal progenitor cells. Molecular and cellular neurosciences. 2003;24(1):23–40. doi: 10.1016/s1044-7431(03)00082-4 14550766.

66. Yan YP, Sailor KA, Vemuganti R, Dempsey RJ. Insulin-like growth factor-1 is an endogenous mediator of focal ischemia-induced neural progenitor proliferation. The European journal of neuroscience. 2006;24(1):45–54. doi: 10.1111/j.1460-9568.2006.04872.x 16882007.

67. Bracko O, Singer T, Aigner S, Knobloch M, Winner B, Ray J, et al. Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J Neurosci. 2012;32(10):3376–87. doi: 10.1523/JNEUROSCI.4248-11.2012 22399759; PubMed Central PMCID: PMC3338187.

68. Wang L, Zhou K, Fu Z, Yu D, Huang H, Zang X, et al. Brain Development and Akt Signaling: the Crossroads of Signaling Pathway and Neurodevelopmental Diseases. Journal of Molecular Neuroscience. 2017;61(3):379–84. doi: 10.1007/s12031-016-0872-y 28025777

69. Juanes M, Guercio G, Marino R, Berensztein E, Warman DM, Ciaccio M, et al. Three novel IGF1R mutations in microcephalic patients with prenatal and postnatal growth impairment. Clinical endocrinology. 2015;82(5):704–11. doi: 10.1111/cen.12555 25040157.

70. Boland E, Clayton-Smith J, Woo VG, McKee S, Manson FDC, Medne L, et al. Mapping of Deletion and Translocation Breakpoints in 1q44 Implicates the Serine/Threonine Kinase AKT3 in Postnatal Microcephaly and Agenesis of the Corpus Callosum. The American Journal of Human Genetics. 2007;81(2):292–303. doi: 10.1086/519999 17668379

71. Chalhoub N, Zhu G, Zhu X, Baker SJ. Cell type specificity of PI3K signaling in Pdk1- and Pten-deficient brains. Genes & Development. 2009;23(14):1619–24. doi: 10.1101/gad.1799609 19605683

72. Easton RM, Cho H, Roovers K, Shineman DW, Mizrahi M, Forman MS, et al. Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size. Molecular and Cellular Biology. 2005;25:1869–78. doi: 10.1128/MCB.25.5.1869-1878.2005 15713641

73. Tschopp O, Yang Z-Z, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T, et al. Essential role of protein kinase Bγ (PKBγ/Akt3) in postnatal brain development but not in glucose homeostasis. Development. 2005;132:2943–54. doi: 10.1242/dev.01864 15930105

74. Cloëtta D, Thomanetz V, Baranek C, Lustenberger RM, Lin S, Oliveri F, et al. Inactivation of mTORC1 in the Developing Brain Causes Microcephaly and Affects Gliogenesis. The Journal of Neuroscience. 2013;33:7799–810. doi: 10.1523/JNEUROSCI.3294-12.2013 23637172

75. Ka M, Condorelli G, Woodgett JR, Kim W-Y. mTOR regulates brain morphogenesis by mediating GSK3 signaling. Development. 2014;141:4076–86. doi: 10.1242/dev.108282 25273085

76. Jansen LA, Mirzaa GM, Ishak GE, O'Roak BJ, Hiatt JB, Roden WH, et al. PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain. 2015;138(6):1613–28. doi: 10.1093/brain/awv045 25722288

77. Tokuda S, Mahaffey CL, Monks B, Faulkner CR, Birnbaum MJ, Danzer SC, et al. A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice. Human Molecular Genetics. 2010;20(5):988–99. doi: 10.1093/hmg/ddq544 21159799

78. Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, et al. Negative Regulation of Neural Stem/Progenitor Cell Proliferation by the <em>Pten</em> Tumor Suppressor Gene in Vivo. Science. 2001;294(5549):2186. doi: 10.1126/science.1065518 11691952

79. Bonaguidi MA, Wheeler MA, Shapiro JS, Stadel RP, Sun GJ, Ming G-l, et al. In Vivo Clonal Analysis Reveals Self-Renewing and Multipotent Adult Neural Stem Cell Characteristics. Cell. 2011;145(7):1142–55. doi: 10.1016/j.cell.2011.05.024 21664664

80. Dumstrei K, Wang F, Hartenstein V. Role of DE-cadherin in neuroblast proliferation, neural morphogenesis, and axon tract formation in Drosophila larval brain development. J Neurosci. 2003;23(8):3325–35. doi: 10.1523/JNEUROSCI.23-08-03325.2003 12716940.

81. Kanai MI, Kim MJ, Akiyama T, Takemura M, Wharton K, O'Connor MB, et al. Regulation of neuroblast proliferation by surface glia in the Drosophila larval brain. Sci Rep. 2018;8(1):3730. doi: 10.1038/s41598-018-22028-y 29487331; PubMed Central PMCID: PMC5829083.

82. Lim DA, Tramontin AD, Trevejo JM, Herrera DG, Garcia-Verdugo JM, Alvarez-Buylla A. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron. 2000;28(3):713–26. doi: 10.1016/s0896-6273(00)00148-3 11163261.

83. Llorens-Bobadilla E, Zhao S, Baser A, Saiz-Castro G, Zwadlo K, Martin-Villalba A. Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury. Cell Stem Cell. 2015;17(3):329–40. doi: 10.1016/j.stem.2015.07.002 26235341

84. Mira H, Andreu Z, Suh H, Lie DC, Jessberger S, Consiglio A, et al. Signaling through BMPR-IA Regulates Quiescence and Long-Term Activity of Neural Stem Cells in the Adult Hippocampus. Cell Stem Cell. 2010;7(1):78–89. doi: 10.1016/j.stem.2010.04.016 20621052.

85. Bonaguidi MA, Peng C-Y, McGuire T, Falciglia G, Gobeske KT, Czeisler C, et al. Noggin Expands Neural Stem Cells in the Adult Hippocampus. Journal of Neuroscience. 2008;28(37):9194–204. doi: 10.1523/JNEUROSCI.3314-07.2008 18784300; PubMed Central PMCID: PMC3651371.

86. Voigt A, Pflanz R, Schafer U, Jackle H. Perlecan participates in proliferation activation of quiescent Drosophila neuroblasts. Developmental dynamics: an official publication of the American Association of Anatomists. 2002;224(4):403–12. doi: 10.1002/dvdy.10120 12203732.

87. Datta S. Control of proliferation activation in quiescent neuroblasts of the Drosophila central nervous system. Development. 1995;121(4):1173–82. 7743929.

88. Park Y, Rangel C, Reynolds MM, Caldwell MC, Johns M, Nayak M, et al. Drosophila perlecan modulates FGF and hedgehog signals to activate neural stem cell division. Dev Biol. 2003;253(2):247–57. doi: 10.1016/s0012-1606(02)00019-2 12645928.

89. Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell. 1991;64(4):841–8. doi: 10.1016/0092-8674(91)90512-w 1847668.

90. Kerever A, Mercier F, Nonaka R, de Vega S, Oda Y, Zalc B, et al. Perlecan is required for FGF-2 signaling in the neural stem cell niche. Stem Cell Research. 2014;12(2):492–505. doi: 10.1016/j.scr.2013.12.009 24434631

91. Ciccolini F, Svendsen CN. Fibroblast growth factor 2 (FGF-2) promotes acquisition of epidermal growth factor (EGF) responsiveness in mouse striatal precursor cells: identification of neural precursors responding to both EGF and FGF-2. J Neurosci. 1998;18(19):7869–80. doi: 10.1523/JNEUROSCI.18-19-07869.1998 9742155.

92. Gritti A, Frolichsthal-Schoeller P, Galli R, Parati EA, Cova L, Pagano SF, et al. Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain. J Neurosci. 1999;19(9):3287–97. doi: 10.1523/JNEUROSCI.19-09-03287.1999 10212288.

93. Ray J, Gage FH. Differential properties of adult rat and mouse brain-derived neural stem/progenitor cells. Mol Cell Neurosci. 2006;31(3):560–73. doi: 10.1016/j.mcn.2005.11.010 16426857.

94. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, et al. Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996;271(25):15292–7. doi: 10.1074/jbc.271.25.15292 8663044.

95. Morante-Redolat JM, Porlan E. Neural Stem Cell Regulation by Adhesion Molecules Within the Subependymal Niche. Frontiers in Cell and Developmental Biology. 2019;7:189. doi: 10.3389/fcell.2019.00189

96. Segarra M, Aburto MR, Cop F, Llaó-Cid C, Härtl R, Damm M, et al. Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system. Science. 2018;361(6404):eaao2861. doi: 10.1126/science.aao2861 30139844.

97. Shen Q, Wang Y, Kokovay E, Lin G, Chuang S-M, Goderie SK, et al. Adult SVZ Stem Cells Lie in a Vascular Niche: A Quantitative Analysis of Niche Cell-Cell Interactions. Cell Stem Cell. 2008;3(3):289–300. doi: 10.1016/j.stem.2008.07.026 18786416; PubMed Central PMCID: PMC2747473.

98. Kazanis I, Lathia JD, Vadakkan TJ, Raborn E, Wan R, Mughal MR, et al. Quiescence and Activation of Stem and Precursor Cell Populations in the Subependymal Zone of the Mammalian Brain Are Associated with Distinct Cellular and Extracellular Matrix Signals. Journal of Neuroscience. 2010;30(29):9771–81. doi: 10.1523/JNEUROSCI.0700-10.2010 20660259; PubMed Central PMCID: PMC3842479.

99. Morizur L, Chicheportiche A, Gauthier LR, Daynac M, Boussin FD, Mouthon M-A. Distinct Molecular Signatures of Quiescent and Activated Adult Neural Stem Cells Reveal Specific Interactions with Their Microenvironment. Stem Cell Reports. 2018;11(2):565–77. doi: 10.1016/j.stemcr.2018.06.005 29983386; PubMed Central PMCID: PMC6092681.

100. Kokovay E, Goderie S, Wang Y, Lotz S, Lin G, Sun Y, et al. Adult SVZ Lineage Cells Home to and Leave the Vascular Niche via Differential Responses to SDF1/CXCR4 Signaling. Cell Stem Cell. 2010;7(2):163–73. doi: 10.1016/j.stem.2010.05.019 20682445; PubMed Central PMCID: PMC2916873.

101. Lai K, Kaspar BK, Gage FH, Schaffer DV. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci. 2003;6(1):21–7. Epub 2002 Dec 2. doi: 10.1038/nn983 12469128.

102. Charytoniuk D, Traiffort E, Hantraye P, Hermel JM, Galdes A, Ruat M. Intrastriatal sonic hedgehog injection increases Patched transcript levels in the adult rat subventricular zone. Eur J Neurosci. 2002;16(12):2351–7. doi: 10.1046/j.1460-9568.2002.02412.x 12492430.

103. Ahn S, Joyner AL. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature. 2005;437(7060):894–7. doi: 10.1038/nature03994 16208373.

104. Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437(7063):1370–5. doi: 10.1038/nature04108 16251967.

105. Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK, et al. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009;136(6):1017–31. doi: 10.1016/j.cell.2008.12.044 19303846; PubMed Central PMCID: PMC2704382.

106. Topol A, Zhu S, Tran N, Simone A, Fang G, Brennand KJ. Altered WNT Signaling in Human Induced Pluripotent Stem Cell Neural Progenitor Cells Derived from Four Schizophrenia Patients. Biol Psychiatry. 2015;78(6):e29–34. doi: 10.1016/j.biopsych.2014.12.028 25708228; PubMed Central PMCID: PMC4520784.

107. Winer JP, Janmey PA, McCormick ME, Funaki M. Bone Marrow-Derived Human Mesenchymal Stem Cells Become Quiescent on Soft Substrates but Remain Responsive to Chemical or Mechanical Stimuli. Tissue Engineering Part A. 2008;15(1):147–54. doi: 10.1089/ten.tea.2007.0388 18673086

108. Ebens AJ, Garren H, Cheyette BN, Zipursky SL. The Drosophila anachronism locus: a glycoprotein secreted by glia inhibits neuroblast proliferation. Cell. 1993;74(1):15–27. doi: 10.1016/0092-8674(93)90291-w 7916657.

109. Ding R, Weynans K, Bossing T, Barros CS, Berger C. The Hippo signalling pathway maintains quiescence in Drosophila neural stem cells. Nature communications. 2016;7:10510. doi: 10.1038/ncomms10510 26821647; PubMed Central PMCID: PMC4740179.

110. Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev. 2016;30(1):1–17. doi: 10.1101/gad.274027.115 26728553; PubMed Central PMCID: PMC4701972.

111. Pan D. The hippo signaling pathway in development and cancer. Developmental cell. 2010;19(4):491–505. doi: 10.1016/j.devcel.2010.09.011 20951342; PubMed Central PMCID: PMC3124840.

112. Harvey K, Tapon N. The Salvador-Warts-Hippo pathway—an emerging tumour-suppressor network. Nature reviews Cancer. 2007;7(3):182–91. doi: 10.1038/nrc2070 17318211.

113. Halder G, Johnson RL. Hippo signaling: growth control and beyond. Development. 2011;138(1):9–22. doi: 10.1242/dev.045500 21138973; PubMed Central PMCID: PMC2998162.

114. Poon CL, Mitchell KA, Kondo S, Cheng LY, Harvey KF. The Hippo Pathway Regulates Neuroblasts and Brain Size in Drosophila melanogaster. Current biology: CB. 2016;26(8):1034–42. doi: 10.1016/j.cub.2016.02.009 26996505.

115. Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot F, Kageyama R. Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation. The EMBO Journal. 1999;18(8):2196–207. doi: 10.1093/emboj/18.8.2196 10205173

116. Ottone C, Krusche B, Whitby A, Clements M, Quadrato G, Pitulescu ME, et al. Direct cell-cell contact with the vascular niche maintains quiescent neural stem cells. Nature Cell Biology. 2014;16(11):1045–56. doi: 10.1038/ncb3045 25283993

117. Breunig JJ, Silbereis J, Vaccarino FM, Šestan N, Rakic P. Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(51):20558–63. doi: 10.1073/pnas.0710156104 18077357; PubMed Central PMCID: PMC2154470.

118. Ables JL, DeCarolis NA, Johnson MA, Rivera PD, Gao Z, Cooper DC, et al. Notch1 Is Required for Maintenance of the Reservoir of Adult Hippocampal Stem Cells. The Journal of Neuroscience. 2010;30(31):10484–92. doi: 10.1523/JNEUROSCI.4721-09.2010 20685991

119. Ehm O, Göritz C, Covic M, Schäffner I, Schwarz TJ, Karaca E, et al. RBPJκ-Dependent Signaling Is Essential for Long-Term Maintenance of Neural Stem Cells in the Adult Hippocampus. The Journal of Neuroscience. 2010;30(41):13794–807. doi: 10.1523/JNEUROSCI.1567-10.2010 20943920

120. Kawaguchi D, Furutachi S, Kawai H, Hozumi K, Gotoh Y. Dll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis. Nature Communications. 2013;4(1):1880. doi: 10.1038/ncomms2895 23695674

121. Fischer-Zirnsak B, Segebrecht L, Schubach M, Charles P, Alderman E, Brown K, et al. Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders. The American Journal of Human Genetics. 2019;105(3):631–9. doi: 10.1016/j.ajhg.2019.07.002 31353024

122. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. Journal of Comparative Neurology. 2000;425(4):479–94. doi: 10.1002/1096-9861(20001002)425:4<479::aid-cne2>3.0.co;2-3 10975875

123. Jackson EL, García-Verdugo JM, Gil-Perotin S, Roy M, Quinones-Hinojosa A, VandenBerg S, et al. PDGFRα-Positive B Cells Are Neural Stem Cells in the Adult SVZ that Form Glioma-like Growths in Response to Increased PDGF Signaling. Neuron. 2006;51(2):187–99. doi: 10.1016/j.neuron.2006.06.012 16846854.

124. Ramírez-Castillejo C, Sánchez-Sánchez F, Andreu-Agulló C, Ferrón SR, Aroca-Aguilar JD, Sánchez P, et al. Pigment epithelium–derived factor is a niche signal for neural stem cell renewal. Nature Neuroscience. 2006;9(3):331–9. doi: 10.1038/nn1657 B45119F9-8C6D-4F0F-B8F4-7C09143E2EC6. 16491078

125. Rosa AI, Gonçalves J, Cortes L, Bernardino L, Malva JO, Agasse F. The Angiogenic Factor Angiopoietin-1 Is a Proneurogenic Peptide on Subventricular Zone Stem/Progenitor Cells. The Journal of Neuroscience. 2010;30(13):4573. doi: 10.1523/JNEUROSCI.5597-09.2010 20357108

126. Lin R, Cai J, Kenyon L, Iozzo R, Rosenwasser R, Iacovitti L. Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain. Stem Cells. 2018;37(3):395–406. doi: 10.1002/stem.2947 30431198

127. Crouch EE, Liu C, Silva-Vargas V, Doetsch F. Regional and Stage-Specific Effects of Prospectively Purified Vascular Cells on the Adult V-SVZ Neural Stem Cell Lineage. Journal of Neuroscience. 2015;35(11):4528–39. doi: 10.1523/JNEUROSCI.1188-14.2015 25788671; PubMed Central PMCID: PMC4363382.

128. Han J, Calvo C-F, Kang TH, Baker KL, Park J-H, Parras C, et al. Vascular Endothelial Growth Factor Receptor 3 Controls Neural Stem Cell Activation in Mice and Humans. Cell Reports. 2015;10(7):1158–72. doi: 10.1016/j.celrep.2015.01.049 25704818; PubMed Central PMCID: PMC4685253.

129. Pereanu W, Shy D, Hartenstein V. Morphogenesis and proliferation of the larval brain glia in Drosophila. Dev Biol. 2005;283(1):191–203. doi: 10.1016/j.ydbio.2005.04.024 15907832.

130. Spéder P, Brand AH. Systemic and local cues drive neural stem cell niche remodelling during neurogenesis in Drosophila. eLife. 2018;7:e30413. doi: 10.7554/eLife.30413 29299997

131. Moss J, Gebara E, Bushong EA, Sánchez-Pascual I, O’Laoi R, El M’Ghari I, et al. Fine processes of Nestin-GFP–positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature. Proceedings of the National Academy of Sciences. 2016;113:E2536–E45. doi: 10.1073/pnas.1514652113 27091993

132. Jang M-H, Bonaguidi MA, Kitabatake Y, Sun J, Song J, Kang E, et al. Secreted Frizzled-Related Protein 3 Regulates Activity-Dependent Adult Hippocampal Neurogenesis. Cell Stem Cell. 2013;12(2):215–23. doi: 10.1016/j.stem.2012.11.021 23395446; PubMed Central PMCID: PMC3569732.

133. Yeh C-Y, Asrican B, Moss J, Quintanilla LJ, He T, Mao X, et al. Mossy Cells Control Adult Neural Stem Cell Quiescence and Maintenance through a Dynamic Balance between Direct and Indirect Pathways. Neuron. 2018;99(3):493–510. doi: 10.1016/j.neuron.2018.07.010 30057205

134. Bao H, Asrican B, Li W, Gu B, Wen Z, Lim S-A, et al. Long-Range GABAergic Inputs Regulate Neural Stem Cell Quiescence and Control Adult Hippocampal Neurogenesis. Cell Stem Cell. 2017;21(5):604–17. doi: 10.1016/j.stem.2017.10.003 29100013

135. Song J, Zhong C, Bonaguidi MA, Sun GJ, Hsu D, Gu Y, et al. Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision. Nature. 2012;489(7414):150–4. doi: 10.1038/nature11306 22842902; PubMed Central PMCID: PMC3438284.

136. Paez-Gonzalez P, Asrican B, Rodriguez E, Kuo CT. Identification of distinct ChAT+ neurons and activity-dependent control of postnatal SVZ neurogenesis. Nature Neuroscience. 2014;17(7):934–42. doi: 10.1038/nn.3734 24880216

137. Tong Cheuk K, Chen J, Cebrián-Silla A, Mirzadeh Z, Obernier K, Guinto Cristina D, et al. Axonal Control of the Adult Neural Stem Cell Niche. Cell Stem Cell. 2014;14(4):500–11. doi: 10.1016/j.stem.2014.01.014 24561083

138. Romero-Grimaldi C, Moreno-López B, Estrada C. Age-dependent effect of nitric oxide on subventricular zone and olfactory bulb neural precursor proliferation. Journal of Comparative Neurology. 2008;506(2):339–46. doi: 10.1002/cne.21556 18022945

139. Merkle FT, Mirzadeh Z, Alvarez-Buylla A. Mosaic Organization of Neural Stem Cells in the Adult Brain. Science. 2007;317(5836):381–4. doi: 10.1126/science.1144914 17615304

140. Huang J, Wang H. Hsp83/Hsp90 Physically Associates with Insulin Receptor to Promote Neural Stem Cell Reactivation. Stem cell reports. 2018;11(4):883–896. doi: 10.1016/j.stemcr.2018.08.014 30245208.

141. Takata Y, Imamura T, Iwata M, Usui I, Haruta T, Nandachi N, et al. Functional importance of heat shock protein 90 associated with insulin receptor on insulin-stimulated mitogenesis. Biochemical and biophysical research communications. 1997;237(2):345–7. doi: 10.1006/bbrc.1997.7116 9268713.

142. Barrott JJ, Haystead TA. Hsp90, an unlikely ally in the war on cancer. FEBS J. 2013;280(6):1381–96. doi: 10.1111/febs.12147 23356585; PubMed Central PMCID: PMC3815692.

143. Pratt WB, Gestwicki JE, Osawa Y, Lieberman AP. Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases. Annu Rev Pharmacol Toxicol. 2015;55:353–71. Epub 2014 Sept 25. doi: 10.1146/annurev-pharmtox-010814-124332 25292434; PubMed Central PMCID: PMC4372135.

144. Callan MA, Clements N, Ahrendt N, Zarnescu DC. Fragile X Protein is required for inhibition of insulin signaling and regulates glial-dependent neuroblast reactivation in the developing brain. Brain Res. 2012;1462:151–61. doi: 10.1016/j.brainres.2012.03.042 22513101.

145. Callan MA, Cabernard C, Heck J, Luois S, Doe CQ, Zarnescu DC. Fragile X protein controls neural stem cell proliferation in the Drosophila brain. Hum Mol Genet. 2010;19(15):3068–79. doi: 10.1093/hmg/ddq213 20504994; PubMed Central PMCID: PMC2901145.

146. Guo W, Zhang L, Christopher DM, Teng ZQ, Fausett SR, Liu C, et al. RNA-binding protein FXR2 regulates adult hippocampal neurogenesis by reducing Noggin expression. Neuron. 2011;70(5):924–38. doi: 10.1016/j.neuron.2011.03.027 21658585; PubMed Central PMCID: PMC3137661.

147. Guo W, Polich ED, Su J, Gao Y, Christopher DM, Allan AM, et al. Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms. Cell Rep. 2015;11(10):1651–66. doi: 10.1016/j.celrep.2015.05.013 26051932; PubMed Central PMCID: PMC4472556.

148. Saffary R, Xie Z. FMRP regulates the transition from radial glial cells to intermediate progenitor cells during neocortical development. J Neurosci. 2011;31(4):1427–39. doi: 10.1523/JNEUROSCI.4854-10.2011 21273427.

149. Ly PT, Tan YS, Koe CT, Zhang Y, Xie G, Endow S, et al. CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation. PLoS Biol. 2019;17(6):e3000276. doi: 10.1371/journal.pbio.3000276 31170139; PubMed Central PMCID: PMC6553684.

150. Li W, Cooper J, Zhou L, Yang C, Erdjument-Bromage H, Zagzag D, et al. Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus. Cancer Cell. 2014;26(1):48–60. doi: 10.1016/j.ccr.2014.05.001 25026211; PubMed Central PMCID: PMC4126592.

151. Martynoga B, Mateo JL, Zhou B, Andersen J, Achimastou A, Urban N, et al. Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence. Genes Dev. 2013;27(16):1769–86. doi: 10.1101/gad.216804.113 23964093; PubMed Central PMCID: PMC3759694.

152. Liu HC, Enikolopov G, Chen Y. Cul4B regulates neural progenitor cell growth. BMC Neurosci. 2012;13:112. doi: 10.1186/1471-2202-13-112 22992378; PubMed Central PMCID: PMC3506489.

153. Cang Y, Zhang J, Nicholas SA, Bastien J, Li B, Zhou P, et al. Deletion of DDB1 in mouse brain and lens leads to p53-dependent elimination of proliferating cells. Cell. 2006;127(5):929–40. doi: 10.1016/j.cell.2006.09.045 17129780.

154. Hu Z, Holzschuh J, Driever W. Loss of DDB1 Leads to Transcriptional p53 Pathway Activation in Proliferating Cells, Cell Cycle Deregulation, and Apoptosis in Zebrafish Embryos. PLoS ONE. 2015;10(7):e0134299. doi: 10.1371/journal.pone.0134299 26225764; PubMed Central PMCID: PMC4520591.

155. Ando H, Sato T, Ito T, Yamamoto J, Sakamoto S, Nitta N, et al. Cereblon Control of Zebrafish Brain Size by Regulation of Neural Stem Cell Proliferation. iScience. 2019;15:95–108. doi: 10.1016/j.isci.2019.04.007 31055217; PubMed Central PMCID: PMC6501120.

156. Vulto-van Silfhout AT, Nakagawa T, Bahi-Buisson N, Haas SA, Hu H, Bienek M, et al. Variants in CUL4B are associated with cerebral malformations. Hum Mutat. 2015;36(1):106–17. Epub 2014 Nov 11. doi: 10.1002/humu.22718 25385192; PubMed Central PMCID: PMC4608231.

157. Badura-Stronka M, Jamsheer A, Materna-Kiryluk A, Sowinska A, Kiryluk K, Budny B, et al. A novel nonsense mutation in CUL4B gene in three brothers with X-linked mental retardation syndrome. Clin Genet. 2010;77(2):141–4. Epub 2009 Dec 10. doi: 10.1111/j.1399-0004.2009.01331.x 20002452.

158. Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, Butler A, et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet. 2007;80(2):345–52. doi: 10.1086/511134 17236139; PubMed Central PMCID: PMC1785336.

159. Zou Y, Liu Q, Chen B, Zhang X, Guo C, Zhou H, et al. Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation. Am J Hum Genet. 2007;80(3):561–6. doi: 10.1086/512489 17273978; PubMed Central PMCID: PMC1821105.

160. Gil-Ranedo J, Gonzaga E, Jaworek KJ, Berger C, Bossing T, Barros CS. STRIPAK Members Orchestrate Hippo and Insulin Receptor Signaling to Promote Neural Stem Cell Reactivation. Cell reports. 2019;27(10):2921–33 e5. doi: 10.1016/j.celrep.2019.05.023 31167138.

161. Hwang J, Pallas DC. STRIPAK complexes: structure, biological function, and involvement in human diseases. Int J Biochem Cell Biol. 2014;47:118–48. Epub 2013 Dec 11. doi: 10.1016/j.biocel.2013.11.021 24333164; PubMed Central PMCID: PMC3927685.

162. Pagenstecher A, Stahl S, Sure U, Felbor U. A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Hum Mol Genet. 2009;18(5):911–8. Epub 2008 Dec 16. doi: 10.1093/hmg/ddn420 19088124; PubMed Central PMCID: PMC2640205.

163. Akong K, McCartney BM, Peifer M. Drosophila APC2 and APC1 have overlapping roles in the larval brain despite their distinct intracellular localizations. Dev Biol. 2002;250(1):71–90. doi: 10.1006/dbio.2002.0777 12297097.

164. Chu-Lagraff Q, Wright DM, McNeil LK, Doe CQ. The prospero gene encodes a divergent homeodomain protein that controls neuronal identity in Drosophila. Development. 1991;Suppl 2:79–85. 1842358.

165. Choksi SP, Southall TD, Bossing T, Edoff K, de Wit E, Fischer BE, et al. Prospero acts as a binary switch between self-renewal and differentiation in Drosophila neural stem cells. Dev Cell. 2006;11:775–89. doi: 10.1016/j.devcel.2006.09.015 17141154.

166. Lai S-L, Doe CQ. Transient nuclear Prospero induces neural progenitor quiescence. eLife. 2014;3:e03363. doi: 10.7554/elife.03363 25354199

167. Li S, Koe CT, Tay ST, Tan ALK, Zhang S, Zhang Y, et al. An intrinsic mechanism controls reactivation of neural stem cells by spindle matrix proteins. Nature Communications. 2017;8(1):122. doi: 10.1038/s41467-017-00172-9 28744001

168. López-Juárez A, Howard J, Ullom K, Howard L, Grande A, Pardo A, et al. Gsx2 controls region-specific activation of neural stem cells and injury-induced neurogenesis in the adult subventricular zone. Genes & Development. 2013;27(11):1272–87. doi: 10.1101/gad.217539.113 23723414; PubMed Central PMCID: PMC3690400.

169. Andersen J, Urbán N, Achimastou A, Ito A, Simic M, Ullom K, et al. A Transcriptional Mechanism Integrating Inputs from Extracellular Signals to Activate Hippocampal Stem Cells. Neuron. 2014;83(5):1085–97. doi: 10.1016/j.neuron.2014.08.004 25189209

170. Niu W, Zou Y, Shen C, Zhang C-L. Activation of Postnatal Neural Stem Cells Requires Nuclear Receptor TLX. Journal of Neuroscience. 2011;31(39):13816–28. doi: 10.1523/JNEUROSCI.1038-11.2011 21957244; PubMed Central PMCID: PMC3192402.

171. Mukherjee S, Brulet R, Zhang L, Hsieh J. REST regulation of gene networks in adult neural stem cells. Nature Communications. 2016;7(1):13360 EP -. doi: 10.1038/ncomms13360 27819263

172. Andersen J, Urban N, Achimastou A, Ito A, Simic M, Ullom K, et al. A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells. Neuron. 2014;83(5):1085–97. doi: 10.1016/j.neuron.2014.08.004 25189209; PubMed Central PMCID: PMC4157576.

173. Imayoshi I, Isomura A, Harima Y, Kawaguchi K, Kori H, Miyachi H, et al. Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science. 2013;342(6163):1203–8. doi: 10.1126/science.1242366 24179156.

174. Sueda R, Imayoshi I, Harima Y, Kageyama R. High Hes1 expression and resultant Ascl1 suppression regulate quiescent vs. active neural stem cells in the adult mouse brain. Genes & Development. 2019;33(9–10):511–23. doi: 10.1101/gad.323196.118 30862661; PubMed Central PMCID: PMC6499325.

175. Urbán N, van den Berg DLC, Forget A, Andersen J, Demmers JAA, Hunt C, et al. Return to quiescence of mouse neural stem cells by degradation of a proactivation protein. Science. 2016;353(6296):292–5. doi: 10.1126/science.aaf4802 27418510

176. Blomfield IM, Rocamonde B, Masdeu MdM, Mulugeta E, Vaga S, van den Berg DLC, et al. Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells. eLife. 2019;8:e48561. doi: 10.7554/eLife.48561 31552825

177. Moortgat S, Berland S, Aukrust I, Maystadt I, Baker L, Benoit V, et al. HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients. European Journal of Human Genetics. 2018;26(1):64–74. doi: 10.1038/s41431-017-0038-6 29180823

178. Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, et al. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nature Genetics. 2009;41(5):535–43. doi: 10.1038/ng.367 19377476

179. Sun G, Yu RT, Evans RM, Shi Y. Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation. Proceedings of the National Academy of Sciences. 2007;104:15282–7.

180. Gao Z, Ure K, Ding P, Nashaat M, Yuan L, Ma J, et al. The Master Negative Regulator REST/NRSF Controls Adult Neurogenesis by Restraining the Neurogenic Program in Quiescent Stem Cells. Journal of Neuroscience. 2011;31(26):9772. doi: 10.1523/JNEUROSCI.1604-11.2011 21715642

181. Paik J-h, Ding Z, Narurkar R, Ramkissoon S, Muller F, Kamoun WS, et al. FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis. Cell Stem Cell. 2009;5(5):540–53. doi: 10.1016/j.stem.2009.09.013 19896444

182. Renault VM, Rafalski VA, Morgan AA, Salih DAM, Brett JO, Webb AE, et al. FoxO3 Regulates Neural Stem Cell Homeostasis. Cell Stem Cell. 2009;5(5):527–39. doi: 10.1016/j.stem.2009.09.014 19896443

183. Ma DK, Marchetto MC, Guo JU, Ming G-l, Gage FH, Song H. Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nature Neuroscience. 2010;13(11):1338–44. doi: 10.1038/nn.2672 20975758

184. Molofsky AV, Pardal R, Iwashita T, Park I-K, Clarke MF, Morrison SJ. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature. 2003;425(6961):962–7. doi: 10.1038/nature02060 14574365

185. Jones KM, Sarić N, Russell JP, Andoniadou CL, Scambler PJ, Basson MA. CHD7 Maintains Neural Stem Cell Quiescence and Prevents Premature Stem Cell Depletion in the Adult Hippocampus. Stem Cells. 2014;33(1):196–210. doi: 10.1002/stem.1822 25183173

186. Fernando RN, Eleuteri B, Abdelhady S, Nussenzweig A, Andäng M, Ernfors P. Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(14):5837–42. doi: 10.1073/pnas.1014993108 21436033

187. Jiang Y, Hsieh J. HDAC3 controls gap 2/mitosis progression in adult neural stem/progenitor cells by regulating CDK1 levels. Proceedings of the National Academy of Sciences. 2014;111(37):13541–6. doi: 10.1073/pnas.1411939111 25161285

188. Zhang J, Ji F, Liu Y, Lei X, Li H, Ji G, et al. Ezh2 Regulates Adult Hippocampal Neurogenesis and Memory. The Journal of Neuroscience. 2014;34(15):5184–99. doi: 10.1523/JNEUROSCI.4129-13.2014 24719098

189. Cheung TH, Rando TA. Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol. 2013;14(6):329–40. doi: 10.1038/nrm3591 23698583; PubMed Central PMCID: PMC3808888.

190. Cheung TH, Rando TA. Molecular regulation of stem cell quiescence. Nature reviews Molecular cell biology. 2013;14(6):329–40. doi: 10.1038/nrm3591 23698583

191. Li L, Clevers H. Coexistence of Quiescent and Active Adult Stem Cells in Mammals. Science. 2010;327(5965):542. doi: 10.1126/science.1180794 20110496

192. Codega P, Silva-Vargas V, Paul A, Maldonado-Soto AR, DeLeo AM, Pastrana E, et al. Prospective Identification and Purification of Quiescent Adult Neural Stem Cells from Their In Vivo Niche. Neuron. 2014;82(3):545–59. doi: 10.1016/j.neuron.2014.02.039 24811379; PubMed Central PMCID: PMC4360885.

193. Shin J, Berg DA, Zhu Y, Shin JY, Song J, Bonaguidi MA, et al. Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis. Cell Stem Cell. 2015;17(3):360–72. doi: 10.1016/j.stem.2015.07.013 26299571.

194. Knobloch M, Pilz G-A, Ghesquière B, Kovacs WJ, Wegleiter T, Moore DL, et al. A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity. Cell Reports. 2017;20(9):2144–55. doi: 10.1016/j.celrep.2017.08.029 28854364

195. Le Belle JE, Orozco NM, Paucar AA, Saxe JP, Mottahedeh J, Pyle AD, et al. Proliferative Neural Stem Cells Have High Endogenous ROS Levels that Regulate Self-Renewal and Neurogenesis in a PI3K/Akt-Dependant Manner. Cell Stem Cell. 2011;8(1):59–71. doi: 10.1016/j.stem.2010.11.028 21211782

196. Chaker Z, Codega P, Doetsch F. A mosaic world: puzzles revealed by adult neural stem cell heterogeneity. Wiley Interdisciplinary Reviews: Developmental Biology. 2016;5(6):640–58. doi: 10.1002/wdev.248 27647730

197. Rushing G, Ihrie RA. Neural stem cell heterogeneity through time and space in the ventricular-subventricular zone. Frontiers in Biology. 2016;11(4):261–84. doi: 10.1007/s11515-016-1407-1 28367160

198. Adams KV, Morshead CM. Neural stem cell heterogeneity in the mammalian forebrain. Progress in Neurobiology. 2018;170:2–36. doi: 10.1016/j.pneurobio.2018.06.005 29902499

199. Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Götz M, et al. Quiescent and Active Hippocampal Neural Stem Cells with Distinct Morphologies Respond Selectively to Physiological and Pathological Stimuli and Aging. Cell Stem Cell. 2010;6(5):445–56. doi: 10.1016/j.stem.2010.03.017 20452319.

200. Otsuki L, Brand AH. Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence. Science. 2018;360(6384):99–102. doi: 10.1126/science.aan8795 29622651.

201. Otsuki L, Brand AH. Dorsal-Ventral Differences in Neural Stem Cell Quiescence Are Induced by p57(KIP2)/Dacapo. Developmental cell. 2019;49(2):293–300 e3. doi: 10.1016/j.devcel.2019.02.015 30905769; PubMed Central PMCID: PMC6486397.

202. Liu TH, Li L, Vaessin H. Transcription of the Drosophila CKI gene dacapo is regulated by a modular array of cis-regulatory sequences. Mech Dev. 2002;112(1–2):25–36. doi: 10.1016/s0925-4773(01)00626-8 11850176.

203. Kippin TE, Martens DJ, van der Kooy D. p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes & Development. 2005;19(6):756–67. doi: 10.1101/gad.1272305 15769947; PubMed Central PMCID: PMC1065728.

204. Andreu Z, Khan MA, Gómez PG, Negueruela S, Hortigüela R, Emeterio JS, et al. The Cyclin‐Dependent Kinase Inhibitor p27kip1 Regulates Radial Stem Cell Quiescence and Neurogenesis in the Adult Hippocampus. Stem Cells. 2015;33(1):219–29. doi: 10.1002/stem.1832 25185890

205. Furutachi S, Matsumoto A, Nakayama KI, Gotoh Y. p57 controls adult neural stem cell quiescence and modulates the pace of lifelong neurogenesis. EMBO J. 2013;32(7):970–81. doi: 10.1038/emboj.2013.50 23481253; PubMed Central PMCID: PMC3616292.

206. Otsuki L, Brand AH. Dorsal-Ventral Differences in Neural Stem Cell Quiescence Are Induced by p57KIP2/Dacapo. Developmental Cell. 2019;49(2):293–300.e3. doi: 10.1016/j.devcel.2019.02.015 30905769

207. Micheli L, D’Andrea G, Ceccarelli M, Ferri A, Scardigli R, Tirone F. p16Ink4a Prevents the Activation of Aged Quiescent Dentate Gyrus Stem Cells by Physical Exercise. Frontiers in Cellular Neuroscience. 2019;13:77. doi: 10.3389/fncel.2019.00077 30899215; PubMed Central PMCID: PMC6374340.

208. Gil-Perotin S, Marin-Husstege M, Li J, Soriano-Navarro M, Zindy F, Roussel MF, et al. Loss of p53 induces changes in the behavior of subventricular zone cells: implication for the genesis of glial tumors. Journal of Neuroscience. 2006;26(4):1107. doi: 10.1523/JNEUROSCI.3970-05.2006 16436596

209. Farnebo M, Bykov VJN, Wiman KG. The p53 tumor suppressor: A master regulator of diverse cellular processes and therapeutic target in cancer. Biochemical and Biophysical Research Communications. 2010;396(1):85–9. doi: 10.1016/j.bbrc.2010.02.152 20494116