MicroRNA-153 improves the neurogenesis of neural stem cells and enhances the cognitive ability of aged mice through the notch signaling pathway


Aging-related cognitive ability impairments are one of the main threats to public health, and impaired hippocampal neurogenesis is a major cause of cognitive decline during aging. However, the regulation of adult neurogenesis in the hippocampus requires further study. Here, we investigated the role of microRNA-153 (miR-153), a highly conserved microRNA in mice and humans, in adult neurogenesis. During the passaging of neural stem cells (NSCs) in vitro, endogenous miR-153 expression was downregulated, with a decrease in neuronal differentiation ability. In addition, miR-153 overexpression increased the neurogenesis of NSCs. Further studies showed that miR-153 regulated neurogenesis by precisely targeting the Notch signaling pathway through inhibition of Jagged1 and Hey2 translation. In vivo analysis demonstrated that miR-153 expression was decreased in the hippocampi of aged mice with impaired cognitive ability, and that miR-153 overexpression in the hippocampus promoted neurogenesis and markedly increased the cognitive abilities of the aged mice. Overall, our findings revealed that miR-153 affected neurogenesis by regulating the Notch signaling pathway and elucidated the function of miR-153 in aging-related, hippocampus-dependent cognitive ability impairments, and neurodegenerative diseases.

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Data availability

The additional data or reagents are available from the corresponding author upon reasonable request.


  1. 1.

    Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20:659–63.

  2. 2.

    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;477:90–94.

  3. 3.

    Ngwenya LB, Heyworth NC, Shwe Y, Moore TL, Rosene DL. Age-related changes in dentate gyrus cell numbers, neurogenesis, and associations with cognitive impairments in the rhesus monkey. Front Syst Neurosci. 2015;9:102.

  4. 4.

    Dennis CV, Suh LS, Rodriguez ML, Kril JJ, Sutherland GT. Human adult neurogenesis across the ages: an immunohistochemical study. Neuropathol Appl Neurobiol. 2016;42:621–38.

  5. 5.

    Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153:1219–27.

  6. 6.

    Kempermann G, Kuhn HG, Gage FH. Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci. 1998;18:3206–12.

  7. 7.

    Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313–7.

  8. 8.

    Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386:493–5.

  9. 9.

    Roy NS, Wang S, Jiang L, Kang J, Benraiss A, Harrison-Restelli C, et al. In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med. 2000;6:271–7.

  10. 10.

    Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA, et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell. 2011;8:566–79.

  11. 11.

    BM J. Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with aging and dementia. A qualitative study. Acta Neuropathol. 1977;37:111–8.

  12. 12.

    Mouton PR, Long JM, Lei DL, Howard V, Jucker M, Calhoun ME, et al. Age and gender effects on microglia and astrocyte numbers in brains of mice. Brain Res. 2002;956:30–35.

  13. 13.

    Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci USA. 2003;100:14385–90.

  14. 14.

    Burghardt NS, Park EH, Hen R, Fenton AA. Adult-born hippocampal neurons promote cognitive flexibility in mice. Hippocampus. 2012;22:1795–808.

  15. 15.

    Szulwach KE, Li XK, Smrt RD, Li YJ, Luo YP, Lin L, et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol. 2010;189:127–U181.

  16. 16.

    Nishino J, Kim I, Chada K, Morrison SJ. Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression. Cell. 2008;135:227–39.

  17. 17.

    Zhao C, Sun G, Li S, Lang MF, Yang S, Li W, et al. MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling. Proc Natl Acad Sci USA. 2010;107:1876–81.

  18. 18.

    Shibata M, Kurokawa D, Nakao H, Ohmura T, Aizawa S. MicroRNA-9 modulates Cajal-Retzius cell differentiation by suppressing Foxg1 expression in mouse medial pallium. J Neurosci. 2008;28:10415–21.

  19. 19.

    Saunders LR, Sharma AD, Tawney J, Nakagawa M, Okita K, Yamanaka S, et al. miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues. Aging (Albany NY). 2010;2:415–31.

  20. 20.

    Packer AN, Xing Y, Harper SQ, Jones L, Davidson BL. The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington’s disease. J Neurosci. 2008;28:14341–6.

  21. 21.

    Zhang Y, Kim MS, Jia B, Yan J, Zuniga-Hertz JP, Han C, et al. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature. 2017;548:52–57.

  22. 22.

    Santa-Maria I, Alaniz ME, Renwick N, Cela C, Fulga TA, Van Vactor D, et al. Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. J Clin Invest. 2015;125:681–6.

  23. 23.

    Tsuyama J, Bunt J, Richards LJ, Iwanari H, Mochizuki Y, Hamakubo T, et al. MicroRNA-153regulates the acquisition of gliogenic competence by neural stem cells. Stem Cell Rep. 2015;5:365–77.

  24. 24.

    Wei C, Salichos L, Wittgrove CM, Rokas A, Patton JG. Transcriptome-wide analysis of small RNA expression in early zebrafish development. RNA. 2012;18:915–29.

  25. 25.

    Zhu TS, Costello MA, Talsma CE, Flack CG, Crowley JG, Hamm LL, et al. Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res. 2011;71:6061–72.

  26. 26.

    Baik SH, Fane M, Park JH, Cheng YL, Fann DYW, Yun UJ, et al. Pin1promotes neuronal death in stroke by stabilizing notch intracellular domain. Ann Neurol. 2015;77:504–16.

  27. 27.

    Grandbarbe L, Bouissac J, Rand M, de Angelis MH, Artavanis-Tsakonas S, Mohier E. Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process. Development. 2003;130:1391–402.

  28. 28.

    Qian X, Shen Q, Goderie SK, He W, Capela A, Davis AA, et al. Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron. 2000;28:69–80.

  29. 29.

    Ebert MS, Sharp PA. MicroRNA sponges: progress and possibilities. Rna-a Publication of the Rna. Society. 2010;16:2043–50.

  30. 30.

    Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods. 2007;4:721–6.

  31. 31.

    Zechner D, Fujita Y, Hulsken J, Muller T, Walther I, Taketo MM, et al. beta-catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev Biol. 2003;258:406–18.

  32. 32.

    Liu XF, Li XY, Zheng PS, Yang WT. DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/beta-catenin pathway via GSK3beta. Cell Death Dis. 2018;9:339.

  33. 33.

    Chi Z, Zhang J, Tokunaga A, Harraz MM, Byrne ST, Dolinko A, et al. Botch promotes neurogenesis by antagonizing Notch. Dev Cell. 2012;22:707–20.

  34. 34.

    Salewski RP, Buttigieg J, Mitchell RA, van der Kooy D, Nagy A, Fehlings MG. The generation of definitive neural stem cells from PiggyBac transposon-induced pluripotent stem cells can be enhanced by induction of the NOTCHsignaling pathway. Stem Cells Dev. 2013;22:383–96.

  35. 35.

    Lindsell CE, Shawber CJ, Boulter J, Weinmaster G. Jagged - a mammalian ligand that activates Notch1. Cell. 1995;80:909–17.

  36. 36.

    Sakamoto M, Hirata H, Ohtsuka T, Bessho Y, Kageyama R. The basic helix-loop-helix genes Hesr1/Hey1 and Hesr2/Hey2 regulate maintenance of neural precursor cells in the brain. J Biol Chem. 2003;278:44808–15.

  37. 37.

    van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature. 2002;415:1030–4.

  38. 38.

    Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang HL, et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014;344:598–602.

  39. 39.

    Li G, Zhang X, Cheng H, Shang X, Xie H, Zhang X, et al. Acupuncture improves cognitive deficits and increases neuron density of the hippocampus in middle-aged SAMP8 mice. Acupunct Med. 2012;30:339–45.

  40. 40.

    Grande A, Sumiyoshi K, Lopez-Juarez A, Howard J, Sakthivel B, Aronow B, et al. Environmental impact on direct neuronal reprogramming in vivo in the adult brain. Nat Commun. 2013;4:2373.

  41. 41.

    Oh HJ, Shin Y, Chung S, Hwang DW, Lee DS. Convective exosome-tracing microfluidics for analysis of cell-non-autonomous neurogenesis. Biomaterials. 2017;112:82–94.

  42. 42.

    Wang R, Dineley KT, Sweatt JD, Zheng H. Presenilin 1 familial Alzheimer’s disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience. 2004;126:305–12.

  43. 43.

    Magnusson JP, Goritz C, Tatarishvili J, Dias DO, Smith EM, Lindvall O, et al. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science. 2014;346:237–41.

  44. 44.

    Rani N, Nowakowski TJ, Zhou H, Godshalk SE, Lisi V, Kriegstein AR, et al. A primate lncRNA mediates notch signaling during neuronal development by sequestering miRNA. Neuron. 2016;90:1174–88.

  45. 45.

    Bonev B, Stanley P, Papalopulu N. MicroRNA-9 modulates Hes1 ultradian oscillations by forming a double-negative feedback loop. Cell Rep. 2012;2:10–8.

  46. 46.

    Shin C, Nam JW, Farh KK, Chiang HR, Shkumatava A, Bartel DP. Expanding the microRNA targeting code: functional sites with centered pairing. Mol Cell. 2010;38:789–802.

  47. 47.

    Iacomino G, Siani A. Role of microRNAs in obesity and obesity-related diseases. Genes Nutr. 2017;12:23.

  48. 48.

    Somel M, Guo S, Fu N, Yan Z, Hu HY, Xu Y, et al. MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain. Genome Res. 2010;20:1207–18.

  49. 49.

    Boekhoorn K, Joels M, Lucassen PJ. Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis. 2006;24:1–14.

  50. 50.

    Mueller SG, Weiner MW. Selective effect of age, Apoe4, and Alzheimer’s disease on hippocampal subfields. Hippocampus. 2009;19:558–64.

  51. 51.

    Li SH, Gao P, Wang LT, Yan YH, Xia Y, Song J, et al. Osthole stimulated neural stem cells differentiation into neurons in an alzheimer’s disease cell model via upregulation of MicroRNA-9 and rescued the functional impairment of hippocampal neurons in APP/PS1 transgenic mice. Front Neurosci. 2017;11:340.

  52. 52.

    Sugaya K. Mechanism of glial differentiation of neural progenitor cells by amyloid precursor protein. Neurodegener Dis. 2008;5:170–2.

  53. 53.

    Ahlenius H, Kokaia Z. Isolation and generation of neurosphere cultures from embryonic and adult mouse brain. Methods Mol Biol. 2010;633:241–52.

  54. 54.

    Li G, Jiapaer Z, Weng R, Hui Y, Jia W, Xi J, et al. Dysregulation of the SIRT1/OCT6 axis contributes to environmental stress-induced neural induction defects. Stem Cell Rep. 2017;8:1270–86.

  55. 55.

    Schildge S, Bohrer C, Beck K, Schachtrup C. Isolation and culture of mouse cortical astrocytes. J Vis Exp. 2013;71:e50079.

  56. 56.

    Guo X, Xu Y, Wang Z, Wu Y, Chen J, Wang G, et al. A Linc1405/Eomes complex promotes cardiac mesoderm specification and cardiogenesis. Cell Stem Cell. 2018;22:893–908 e896.

  57. 57.

    Xi J, Wu Y, Li G, Ma L, Feng K, Guo X, et al. Mir-29b mediates the neural tube versus neural crest fate decision during embryonic stem cell neural differentiation. Stem Cell Rep. 2017;9:571–86.

  58. 58.

    Yang D, Qiao J, Wang G, Lan Y, Li G, Guo X, et al. N6-Methyladenosine modification of lincRNA 1281 is critically required for mESC differentiation potential. Nucleic Acids Res. 2018;46:3906–20.

  59. 59.

    Guo XD, Liu QD, Wang GY, Zhu SC, Gao LF, Hong WJ, et al. microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming. Cell Res. 2013;23:142–56.

  60. 60.

    Chen W, Liu N, Zhang H, Zhang H, Qiao J, Jia W, et al. Sirt6 promotes DNA end joining in iPSCs derived from old mice. Cell Rep. 2017;18:2880–92.

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This work was supported by the Ministry of Science and Technology (grant 2016YFA0101300), the National Natural Science Foundation of China (grants 81530042, 31721003, 31871495, 31571529, 31571519, 31701110, and 31671533), and Shanghai Municipal Medical and Health Discipline Construction Projects (grant 2017ZZ02015).

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The author contributions can be found in the Supplementary Material. All authors read and approved the final paper.

Correspondence to Jiajie Xi or Jiuhong Kang.

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