Fate Specification of Neural Stem Cells


Neural stem cells (NSCs) possess the ability to self-renew and to ­differentiate along neuronal and glial lineages. At the molecular level, these ­processes are currently defined in terms of a dynamic interplay between extracellular cues, including cytokine signaling, and intracellular programs such as epigenetic modification, including histone methylation and acetylation and DNA methylation. This review discusses recent advances in our understanding of the molecular mechanisms that control the specification of neuronal, astroglial, and oligodendroglial fates in NSCs of the developing and adult central nervous system.


Leukemia Inhibitory Factor Fate Specification Glial Fibrillary Acidic Protein Expression bHLH Protein Oligodendrocyte Differentiation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Dr. Ian Smith for helpful comments and critical reading of the manuscript. We are very grateful to M. Ueda for her excellent secretarial assistance.


  1. Akazawa C, Sasai Y, Nakanishi S et al (1992) Molecular characterization of a rat negative regulator with a basic helix-loop-helix structure predominantly expressed in the developing nervous system. J Biol Chem 267:21879–21885.PubMedGoogle Scholar
  2. Andres ME, Burger C, Peral-Rubio MJ et al (1999) CoREST: a functional corepressor required for regulation of neural-specific gene expression. Proc Natl Acad Sci USA 96:9873–9878.PubMedGoogle Scholar
  3. Ballas N, Mandel G (2005) The many faces of REST oversee epigenetic programming of neuronal genes. Curr Opin Neurobiol 15:500–506.PubMedGoogle Scholar
  4. Ballas N, Grunseich C, Lu DD et al (2005) REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121:645–657.PubMedGoogle Scholar
  5. Battaglioli E, Andres ME, Rose DW et al (2002) REST repression of neuronal genes requires components of the hSWI.SNF complex. J Biol Chem 277:41038–41045.PubMedGoogle Scholar
  6. Bertrand N, Castro DS, Guillemot F (2002) Proneural genes and the specification of neural cell types. Nat Rev Neurosci 3:517–530.PubMedGoogle Scholar
  7. Bonni A, Sun Y, Nadal-Vicens M et al (1997) Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278:477–483.PubMedGoogle Scholar
  8. Buffo A, Vosko MR, Erturk D et al (2005) Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. Proc Natl Acad Sci USA 102:18183–18188.PubMedGoogle Scholar
  9. Cameron HA, Woolley CS, McEwen BS et al (1993) Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56:337–344.PubMedGoogle Scholar
  10. Campbell K (2005) Cortical neuron specification: it has its time and place. Neuron 46:373–376.PubMedGoogle Scholar
  11. Cebolla B, Vallejo M (2006) Nuclear factor-I regulates glial fibrillary acidic protein gene expression in astrocytes differentiated from cortical precursor cells. J Neurochem 97:1057–1070.PubMedGoogle Scholar
  12. Chambers CB, Peng Y, Nguyen H et al (2001) Spatiotemporal selectivity of response to Notch1 signals in mammalian forebrain precursors. Development (Camb) 128:689–702.Google Scholar
  13. Chen H, Thiagalingam A, Chopra H et al (1997) Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression. Proc Natl Acad Sci USA 94:5355–5360.PubMedGoogle Scholar
  14. Chong JA, Tapia-Ramirez J, Kim S et al (1995) REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80:949–957.PubMedGoogle Scholar
  15. Christopherson KS, Ullian EM, Stokes CC et al (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–433.PubMedGoogle Scholar
  16. Conaco C, Otto S, Han JJ et al (2006) Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci USA 103:2422–2427.PubMedGoogle Scholar
  17. das Neves L, Duchala CS, Tolentino-Silva F et al (1999) Disruption of the murine nuclear factor I-A gene (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum. Proc Natl Acad Sci USA 96:11946–11951.Google Scholar
  18. de la Serna IL, Ohkawa Y, Imbalzano AN (2006) Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers. Nat Rev Genet 7:461–473.PubMedGoogle Scholar
  19. Deneen B, Ho R, Lukaszewicz A et al (2006) The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52:953–968.PubMedGoogle Scholar
  20. Doetsch F (2003) The glial identity of neural stem cells. Nat Neurosci 6:1127–1134.PubMedGoogle Scholar
  21. Elson GC, Lelievre E, Guillet C et al (2000) CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex. Nat Neurosci 3:867–872.PubMedGoogle Scholar
  22. Fan G, Martinowich K, Chin MH et al (2005) DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development (Camb) 132:3345–3356.Google Scholar
  23. Fukuda S, Kondo T, Takebayashi H et al (2004) Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway. Cell Death Differ 11:196–202.PubMedGoogle Scholar
  24. Furukawa T, Mukherjee S, Bao ZZ et al (2000) rax, Hes1, and notch1 promote the formation of Muller glia by postnatal retinal progenitor cells. Neuron 26:383–394.PubMedGoogle Scholar
  25. Furusho M, Ono K, Takebayashi H et al (2006) Involvement of the Olig2 transcription factor in cholinergic neuron development of the basal forebrain. Dev Biol 293:348–357.PubMedGoogle Scholar
  26. Gabay L, Lowell S, Rubin LL et al (2003) Deregulation of dorsoventral patterning by FGF confers trilineage differentiation capacity on CNS stem cells in vitro. Neuron 40:485–499.PubMedGoogle Scholar
  27. Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438.PubMedGoogle Scholar
  28. Gage FH, Kempermann G, Palmer TD et al (1998) Multipotent progenitor cells in the adult dentate gyrus. J Neurobiol 36:249–266.PubMedGoogle Scholar
  29. Garcia-Verdugo JM, Doetsch F, Wichterle H et al (1998) Architecture and cell types of the adult subventricular zone: in search of the stem cells. J Neurobiol 36:234–248.PubMedGoogle Scholar
  30. Ge W, Martinowich K, Wu X et al (2002) Notch signaling promotes astrogliogenesis via direct CSL-mediated glial gene activation. J Neurosci Res 69:848–860.PubMedGoogle Scholar
  31. Grandbarbe L, Bouissac J, Rand M et al (2003) Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process. Development (Camb) 130:1391–1402.Google Scholar
  32. Gronostajski RM (2000) Roles of the NFI/CTF gene family in transcription and development. Gene (Amst) 249:31–45.Google Scholar
  33. Gross RE, Mehler MF, Mabie PC et al (1996) Bone morphogenetic proteins promote astroglial lineage commitment by mammalian subventricular zone progenitor cells. Neuron 17:595–606.PubMedGoogle Scholar
  34. He F, Ge W, Martinowich K et al (2005) A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci 8:616–625.PubMedGoogle Scholar
  35. He Y, Dupree J, Wang J et al (2007) The transcription factor Yin Yang 1 is essential for oligodendrocyte progenitor differentiation. Neuron 55:217–230.PubMedGoogle Scholar
  36. Hermanson O, Jepsen K, Rosenfeld MG (2002) N-CoR controls differentiation of neural stem cells into astrocytes. Nature (Lond) 419:934–939.Google Scholar
  37. Hirabayashi Y, Itoh Y, Tabata H et al (2004) The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development (Camb) 131:2791–2801.Google Scholar
  38. Hsieh J, Gage FH (2004) Epigenetic control of neural stem cell fate. Curr Opin Genet Dev 14:461–469.PubMedGoogle Scholar
  39. Hsieh J, Nakashima K, Kuwabara T et al (2004a) Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci USA 101:16659–16664.PubMedGoogle Scholar
  40. Hsieh J, Aimone JB, Kaspar BK et al (2004b) IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. J Cell Biol 164:111–122.PubMedGoogle Scholar
  41. Israsena N, Hu M, Fu W et al (2004) The presence of FGF2 signaling determines whether beta-catenin exerts effects on proliferation or neuronal differentiation of neural stem cells. Dev Biol 268:220–231.PubMedGoogle Scholar
  42. Jackson EL, Garcia-Verdugo JM, Gil-Perotin S et al (2006) PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51:187–199.PubMedGoogle Scholar
  43. Kettenmann H, Ransom BR (1988) Electrical coupling between astrocytes and between oligodendrocytes studied in mammalian cell cultures. Glia 1:64–73.PubMedGoogle Scholar
  44. Kohyama J, Tokunaga A, Fujita Y et al (2005) Visualization of spatiotemporal activation of Notch signaling: live monitoring and significance in neural development. Dev Biol 286:311–325.PubMedGoogle Scholar
  45. Kuwabara T, Hsieh J, Nakashima K et al (2004) A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 116:779–793.PubMedGoogle Scholar
  46. Ledent V, Paquet O, Vervoort M (2002) Phylogenetic analysis of the human basic helix-loop-helix proteins. Genome Biol 3:RESEARCH0030.Google Scholar
  47. Lee JC, Mayer-Proschel M, Rao MS (2000) Gliogenesis in the central nervous system. Glia 30:105–121.PubMedGoogle Scholar
  48. Lee SK, Lee B, Ruiz EC et al (2005) Olig2 and Ngn2 function in opposition to modulate gene expression in motor neuron progenitor cells. Genes Dev 19:282–294.PubMedGoogle Scholar
  49. Lelievre E, Plun-Favreau H, Chevalier S et al (2001) Signaling pathways recruited by the cardiotrophin-like cytokine/cytokine-like factor-1 composite cytokine: specific requirement of the membrane-bound form of ciliary neurotrophic factor receptor alpha component. J Biol Chem 276:22476–22484.PubMedGoogle Scholar
  50. Lessard J, Wu JI, Ranish JA et al (2007) An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55:201–215.PubMedGoogle Scholar
  51. Li W, Cogswell CA, LoTurco JJ (1998) Neuronal differentiation of precursors in the neocortical ventricular zone is triggered by BMP. J Neurosci 18:8853–8862.PubMedGoogle Scholar
  52. Lim DA, Tramontin AD, Trevejo JM et al (2000) Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28:713–726.PubMedGoogle Scholar
  53. Lindvall O, Kokaia Z (2006) Stem cells for the treatment of neurological disorders. Nature 441:1094–1096.PubMedGoogle Scholar
  54. Lu QR, Yuk D, Alberta JA et al (2000) Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 25:317–329.PubMedGoogle Scholar
  55. Lu QR, Sun T, Zhu Z et al (2002) Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109:75–86.PubMedGoogle Scholar
  56. Machon O, van den Bout CJ, Backman M et al (2003) Role of beta-catenin in the developing cortical and hippocampal neuroepithelium. Neuroscience 122:129–143.PubMedGoogle Scholar
  57. Marin-Husstege M, Muggironi M, Liu A et al (2002) Histone deacetylase activity is necessary for oligodendrocyte lineage progression. J Neurosci 22:10333–10345.PubMedGoogle Scholar
  58. Marshall CA, Novitch BG, Goldman JE (2005) Olig2 directs astrocyte and oligodendrocyte formation in postnatal subventricular zone cells. J Neurosci 25:7289–7298.PubMedGoogle Scholar
  59. Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250.PubMedGoogle Scholar
  60. Molofsky AV, Pardal R, Morrison SJ (2004) Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol 16:700–707.PubMedGoogle Scholar
  61. Moore KB, Schneider ML, Vetter ML (2002) Posttranslational mechanisms control the timing of bHLH function and regulate retinal cell fate. Neuron 34:183–195.PubMedGoogle Scholar
  62. Morrison SJ, Perez SE, Qiao Z et al (2000) Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 101:499–510.PubMedGoogle Scholar
  63. Muroyama Y, Fujiwara Y, Orkin SH et al (2005) Specification of astrocytes by bHLH protein SCL in a restricted region of the neural tube. Nature 438:360–363.PubMedGoogle Scholar
  64. Murre C, McCaw PS, Vaessin H et al (1989) Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell 58:537–544.PubMedGoogle Scholar
  65. Nakashima K, Yanagisawa M, Arakawa et al (1999) Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284:479–482.Google Scholar
  66. Nakashima K, Takizawa T, Ochiai W et al (2001) BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proc Natl Acad Sci USA 98:5868–5873.PubMedGoogle Scholar
  67. Namihira M, Nakashima K, Taga T (2004) Developmental stage dependent regulation of DNA methylation and chromatin modification in a immature astrocyte specific gene promoter. FEBS Lett 572:184–188.PubMedGoogle Scholar
  68. Nery S, Wichterle H, Fishell G (2001) Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. Development 128:527–540.PubMedGoogle Scholar
  69. Noctor SC, Martinez-Cerdeno V, Ivic L et al (2004) Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 7:136–144.PubMedGoogle Scholar
  70. Norton JD, Deed RW, Craggs G et al (1998) Id helix-loop-helix proteins in cell growth and differentiation. Trends Cell Biol 8:58–65.PubMedGoogle Scholar
  71. Ohtsuka T, Ishibashi M, Gradwohl G et al (1999) Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J 18:2196–2207.PubMedGoogle Scholar
  72. Okano H (2002) Stem cell biology of the central nervous system. J Neurosci Res 69:698–707.PubMedGoogle Scholar
  73. Park IH, Zhao R, West JA et al (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146.PubMedGoogle Scholar
  74. Pringle NP, Guthrie S, Lumsden A et al (1998) Dorsal spinal cord neuroepithelium generates astrocytes but not oligodendrocytes. Neuron 20:883–893.PubMedGoogle Scholar
  75. Qian X, Shen Q, Goderie SK et al (2000) Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28:69–80.PubMedGoogle Scholar
  76. Robertson KD, Jones PA (2000) DNA methylation: past, present and future directions. Carcinogenesis 21:461–467.Google Scholar
  77. Roopra A, Sharling L, Wood IC et al (2000) Transcriptional repression by neuron-restrictive silencer factor is mediated via the Sin3-histone deacetylase complex. Mol Cell Biol 20:2147–2157.PubMedGoogle Scholar
  78. Ross SE, Greenberg ME, Stiles CD (2003) Basic helix-loop-helix factors in cortical development. Neuron 39:13–25.PubMedGoogle Scholar
  79. Samanta J, Kessler JA (2004) Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation. Development 131:4131–4142.PubMedGoogle Scholar
  80. Sauvageot CM, Stiles CD (2002) Molecular mechanisms controlling cortical gliogenesis. Curr Opin Neurobiol 12:244–249.PubMedGoogle Scholar
  81. Schoenherr CJ, Anderson DJ (1995) The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267:1360–1363.PubMedGoogle Scholar
  82. Schoenherr CJ, Paquette AJ, Anderson DJ (1996) Identification of potential target genes for the neuron-restrictive silencer factor. Proc Natl Acad Sci USA 93:9881–9886.PubMedGoogle Scholar
  83. Seo S, Herr A, Lim JW et al (2005) Geminin regulates neuronal differentiation by antagonizing Brg1 activity. Genes Dev 19:1723–1734.PubMedGoogle Scholar
  84. Seto E, Shi Y, Shenk T (1991) YY1 is an initiator sequence-binding protein that directs and activates transcription in vitro. Nature 354:241–245.PubMedGoogle Scholar
  85. Setoguchi T, Kondo T (2004) Nuclear export of OLIG2 in neural stem cells is essential for ciliary neurotrophic factor-induced astrocyte differentiation. J Cell Biol 166:963–968.PubMedGoogle Scholar
  86. Shen S, Li J, Casaccia-Bonnefil P (2005) Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain. J Cell Biol 169:577–589.PubMedGoogle Scholar
  87. Shu T, Butz KG, Plachez C et al (2003) Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice. J Neurosci 23:203–212.PubMedGoogle Scholar
  88. Song MR, Ghosh A (2004) FGF2-induced chromatin remodeling regulates CNTF-mediated gene expression and astrocyte differentiation. Nat Neurosci 7:229–235.PubMedGoogle Scholar
  89. Steele-Perkins G, Plachez C, Butz KG et al (2005) The transcription factor gene Nfib is essential for both lung maturation and brain development. Mol Cell Biol 25:685–698.PubMedGoogle Scholar
  90. Stolt CC, Lommes P, Sock E et al (2003) The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev 17:1677–1689.PubMedGoogle Scholar
  91. Sun Y, Nadal-Vicens M, Misono S et al (2001) Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104:365–376.PubMedGoogle Scholar
  92. Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819.PubMedGoogle Scholar
  93. Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872.PubMedGoogle Scholar
  94. Takebayashi H, Yoshida S, Sugimori M et al (2000) Dynamic expression of basic helix-loop-helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3. Mech Dev 99:143–148.PubMedGoogle Scholar
  95. Takebayashi H, Nabeshima Y, Yoshida S et al (2002) The basic helix-loop-helix factor olig2 is essential for the development of motoneuron and oligodendrocyte lineages. Curr Biol 12:1157–1163.PubMedGoogle Scholar
  96. Takizawa T, Nakashima K, Namihira M et al (2001) DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Dev Cell 1:749–758.PubMedGoogle Scholar
  97. Takizawa T, Ochiai W, Nakashima K et al (2003) Enhanced gene activation by Notch and BMP signaling cross-talk. Nucleic Acids Res 31:5723–5731.PubMedGoogle Scholar
  98. Tanigaki K, Nogaki F, Takahashi J et al (2001) Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate. Neuron 29:45–55.PubMedGoogle Scholar
  99. Temple S (2001) The development of neural stem cells. Nature 414:112–117.PubMedGoogle Scholar
  100. Thomas MJ, Seto E (1999) Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key? Gene 236:197–208.PubMedGoogle Scholar
  101. Tokunaga A, Kohyama J, Yoshida T et al (2004) Mapping spatio-temporal activation of Notch signaling during neurogenesis and gliogenesis in the developing mouse brain. J Neurochem 90:142–154.PubMedGoogle Scholar
  102. Vinals F, Reiriz J, Ambrosio S et al (2004) BMP-2 decreases Mash1 stability by increasing Id1 expression. EMBO J 23:3527–3537.PubMedGoogle Scholar
  103. Wrana JL (2000) Regulation of Smad activity. Cell 100:189–192.PubMedGoogle Scholar
  104. Yant SR, Zhu W, Millinoff D et al (1995) High affinity YY1 binding motifs: identification of two core types (ACAT and CCAT) and distribution of potential binding sites within the human beta globin cluster. Nucleic Acids Res 23:4353–4362.PubMedGoogle Scholar
  105. Yoder JA, Walsh CP, Bestor TH (1997) Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13:335–340.PubMedGoogle Scholar
  106. Yung SY, Gokhan S, Jurcsak J et al (2002) Differential modulation of BMP signaling promotes the elaboration of cerebral cortical GABAergic neurons or oligodendrocytes from a common sonic hedgehog-responsive ventral forebrain progenitor species. Proc Natl Acad Sci USA 99:16273–16278.PubMedGoogle Scholar
  107. Zhou Q, Anderson DJ (2002) The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109:61–73.PubMedGoogle Scholar
  108. Zhou Q, Wang S, Anderson DJ (2000) Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron 25:331–343.PubMedGoogle Scholar

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© Springer 2011

Authors and Affiliations

  1. 1.Laboratory of Molecular NeuroscienceGraduate School of Biological Sciences, Nara Institute of Science and TechnologyIkomaJapan

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