Cellular and Molecular Life Sciences

, Volume 73, Issue 21, pp 4019–4042 | Cite as

Hes1: the maestro in neurogenesis

  • Sivadasan Bindu Dhanesh
  • Chandramohan Subashini
  • Jackson James


The process of neurogenesis is well orchestrated by the harmony of multiple cues in a spatiotemporal manner. In this review, we focus on how a dynamic gene, Hes1, is involved in neurogenesis with the view of its regulation and functional implications. Initially, we have reviewed the immense functional significance drawn by this maestro during neural development in a context-dependent manner. How this indispensable role of Hes1 in conferring the competency for neural differentiation partly relies on the direct/indirect mode of repression mediated by very specific structural and functional arms of this protein has also been outlined here. We also review the detailed molecular mechanisms behind the well-tuned oscillatory versus sustained expression of this antineurogenic bHLH repressor, which indeed makes it a master gene to implement the elusive task of neural progenitor propensity. Apart from the functional aspects of Hes1, we also discuss the molecular insights into the endogenous regulatory machinery that regulates its expression. Though Hes1 is a classical target of the Notch signaling pathway, we discuss here its differential expression at the molecular, cellular, and/or regional level. Moreover, we describe how its expression is fine-tuned by all possible ways of gene regulation such as epigenetic, transcriptional, post-transcriptional, post-translational, and environmental factors during vertebrate neurogenesis.


Notch signaling Neural stem cell Neural progenitor Gliogenesis Oscillation CNS development 



Hairy and enhancer of split


Brain lipid-binding protein


Notch intracellular domain


Recombination signal binding protein for immunoglobulin kappa J region


N-[N-(3,5-difluoro-phenacetyl-l-alanyl]-S-phenylglycine tert-butyl ester


Fibroblast growth factor


C-Jun N-terminal kinase


Activating transcription factor 2


Epidermal growth factor


Mitogen-activated protein kinase


Extracellular signal-regulated kinases


Sonic hedgehog


Activator protein 1


Basic helix-loop-helix



ES cells

Embryonic stem cells


Bone morphogenetic protein


Leukemia inhibitory factor


Janus kinase


Reactive oxygen species




T-cell leukemia homeobox protein 3


Cyclin-dependent kinase


Gamma-aminobutyric acid




Platelet-derived growth factor


Vascular endothelial growth factor


Retinal ganglion cell


Signal transducer and activator of transcription


Ciliary neurotrophic factor


Nerve growth factor


Transforming growth factor beta 1

Amyloid beta


DNA methyltransferase


Dorsal root ganglion


Paired box 3


Phosphatidylinositol 3 kinase


LIM homeobox 2


Ventricular zone


Subventricular zone


Chloramphenicol acetyltransferase


Transducin-like enhancer of split


Nuclear factor IA


Locked nucleic acid


Ca2+/calmodulin-dependent protein kinase II delta


Poly [ADP-ribose] polymerase 1


Protein kinase C


Deubiquitinating enzymes




Docosahexaenoic acid


Eicosapentaenoic acid


Microtubule-associated protein 2


Glial fibrillary acidic protein


S100 calcium-binding protein Β


Cerebellar granule neurons


α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor


Alzheimer’s disease


Zona limitans intrathalamica


Central nervous system


Peripheral nervous system


Neuroepithelial progenitors


Inhibitors of differentiation


Neural progenitor cell



This work was supported by Intramural Grants to J.J. from Rajiv Gandhi Centre for Biotechnology (RGCB) and external funding from Department of Biotechnology, Government of India (BT/PR4919/MED/30/787/2012). S.B.D. (09/716[0126]/2009-EMR-1) and C.S (20-06/2010(i)EU-IV) were supported by research fellowship from Council for Scientific and Industrial Research (CSIR), Government of India.


  1. 1.
    Schuurmans C, Guillemot F (2002) Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr Opin Neurobiol 12(1):26–34PubMedCrossRefGoogle Scholar
  2. 2.
    Hevner RF, Hodge RD, Daza RA, Englund C (2006) Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res 55(3):223–233PubMedCrossRefGoogle Scholar
  3. 3.
    Guillemot F (2007) Spatial and temporal specification of neural fates by transcription factor codes. Development 134(21):3771–3780PubMedCrossRefGoogle Scholar
  4. 4.
    Wen S, Li H, Liu J (2009) Dynamic signaling for neural stem cell fate determination. Cell Adh Migr 3(1):107–117PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD (2007) Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci 8(6):427–437PubMedCrossRefGoogle Scholar
  6. 6.
    Guillemot F (2007) Cell fate specification in the mammalian telencephalon. Prog Neurobiol 83(1):37–52PubMedCrossRefGoogle Scholar
  7. 7.
    Ohnuma S, Philpott A, Harris WA (2001) Cell cycle and cell fate in the nervous system. Curr Opin Neurobiol 11(1):66–73PubMedCrossRefGoogle Scholar
  8. 8.
    Cremisi F, Philpott A, Ohnuma S (2003) Cell cycle and cell fate interactions in neural development. Curr Opin Neurobiol 13(1):26–33PubMedCrossRefGoogle Scholar
  9. 9.
    Huttner WB, Kosodo Y (2005) Symmetric versus asymmetric cell division during neurogenesis in the developing vertebrate central nervous system. Curr Opin Cell Biol 17(6):648–657PubMedCrossRefGoogle Scholar
  10. 10.
    Zhong W, Chia W (2008) Neurogenesis and asymmetric cell division. Curr Opin Neurobiol 18(1):4–11PubMedCrossRefGoogle Scholar
  11. 11.
    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770–776PubMedCrossRefGoogle Scholar
  12. 12.
    Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137(2):216–233PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138(17):3593–3612PubMedCrossRefGoogle Scholar
  14. 14.
    Pierfelice T, Alberi L, Gaiano N (2011) Notch in the vertebrate nervous system: an old dog with new tricks. Neuron 69(5):840–855PubMedCrossRefGoogle Scholar
  15. 15.
    Kageyama R, Ohtsuka T (1999) The Notch-Hes pathway in mammalian neural development. Cell Res 9(3):179–188PubMedCrossRefGoogle Scholar
  16. 16.
    Borggrefe T, Oswald F (2009) The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 66(10):1631–1646PubMedCrossRefGoogle Scholar
  17. 17.
    Iso T, Kedes L, Hamamori Y (2003) HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194(3):237–255PubMedCrossRefGoogle Scholar
  18. 18.
    Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7(9):678–689PubMedCrossRefGoogle Scholar
  19. 19.
    Fischer A, Gessler M (2007) Delta–Notch–and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Res 35(14):4583–4596PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Ishibashi M, Ang SL, Shiota K, Nakanishi S, Kageyama R, Guillemot F (1995) Targeted disruption of mammalian hairy and enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev 9(24):3136–3148PubMedCrossRefGoogle Scholar
  21. 21.
    Nakamura Y, Sakakibara S, Miyata T, Ogawa M, Shimazaki T, Weiss S, Kageyama R, Okano H (2000) The bHLH gene hes1 as a repressor of the neuronal commitment of CNS stem cells. J Neurosci 20(1):283–293PubMedGoogle Scholar
  22. 22.
    Ohtsuka T, Sakamoto M, Guillemot F, Kageyama R (2001) Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. J Biol Chem 276(32):30467–30474PubMedCrossRefGoogle Scholar
  23. 23.
    Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot F, Kageyama R (1999) Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J 18(8):2196–2207PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Baek JH, Hatakeyama J, Sakamoto S, Ohtsuka T, Kageyama R (2006) Persistent and high levels of Hes1 expression regulate boundary formation in the developing central nervous system. Development 133(13):2467–2476PubMedCrossRefGoogle Scholar
  25. 25.
    Kageyama R, Ohtsuka T, Kobayashi T (2008) Roles of Hes genes in neural development. Dev Growth Differ 50(Suppl 1):S97–S103PubMedCrossRefGoogle Scholar
  26. 26.
    Kageyama R, Ohtsuka T, Kobayashi T (2007) The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development 134(7):1243–1251PubMedCrossRefGoogle Scholar
  27. 27.
    Shimojo H, Ohtsuka T, Kageyama R (2011) Dynamic expression of notch signaling genes in neural stem/progenitor cells. Front Neurosci 5:78PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Harima Y, Imayoshi I, Shimojo H, Kobayashi T, Kageyama R (2014) The roles and mechanism of ultradian oscillatory expression of the mouse Hes genes. Semin Cell Dev Biol 34:85–90PubMedCrossRefGoogle Scholar
  29. 29.
    Kobayashi T, Kageyama R (2014) Expression dynamics and functions of Hes factors in development and diseases. Curr Top Dev Biol 110:263–283PubMedCrossRefGoogle Scholar
  30. 30.
    Hatakeyama J, Bessho Y, Katoh K, Ookawara S, Fujioka M, Guillemot F, Kageyama R (2004) Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131(22):5539–5550PubMedCrossRefGoogle Scholar
  31. 31.
    Takatsuka K, Hatakeyama J, Bessho Y, Kageyama R (2004) Roles of the bHLH gene Hes1 in retinal morphogenesis. Brain Res 1004(1–2):148–155PubMedCrossRefGoogle Scholar
  32. 32.
    Lee HY, Wroblewski E, Philips GT, Stair CN, Conley K, Reedy M, Mastick GS, Brown NL (2005) Multiple requirements for Hes 1 during early eye formation. Dev Biol 284(2):464–478PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R (2005) Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res 306(2):343–348PubMedCrossRefGoogle Scholar
  34. 34.
    Yan CH, Levesque M, Claxton S, Johnson RL, Ang SL (2011) Lmx1a and lmx1b function cooperatively to regulate proliferation, specification, and differentiation of midbrain dopaminergic progenitors. J Neurosci 31(35):12413–12425PubMedCrossRefGoogle Scholar
  35. 35.
    Boshnjaku V, Ichi S, Shen YW, Puranmalka R, Mania-Farnell B, McLone DG, Tomita T, Mayanil CS (2011) Epigenetic regulation of sensory neurogenesis in the dorsal root ganglion cell line ND7 by folic acid. Epigenetics 6(10):1207–1216PubMedCrossRefGoogle Scholar
  36. 36.
    Julian E, Dave RK, Robson JP, Hallahan AR, Wainwright BJ (2010) Canonical Notch signaling is not required for the growth of Hedgehog pathway-induced medulloblastoma. Oncogene 29(24):3465–3476PubMedCrossRefGoogle Scholar
  37. 37.
    Ishibashi M, Moriyoshi K, Sasai Y, Shiota K, Nakanishi S, Kageyama R (1994) Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system. EMBO J 13(8):1799–1805PubMedPubMedCentralGoogle Scholar
  38. 38.
    Haragopal H, Yu D, Zeng X, Kim SW, Han IB, Ropper AE, Anderson JE, Teng YD (2015) Stemness enhancement of human neural stem cells following bone marrow MSC coculture. Cell Transpl 24(4):645–659CrossRefGoogle Scholar
  39. 39.
    Ju BG, Solum D, Song EJ, Lee KJ, Rose DW, Glass CK, Rosenfeld MG (2004) Activating the PARP-1 sensor component of the groucho/TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway. Cell 119(6):815–829PubMedCrossRefGoogle Scholar
  40. 40.
    Lin CH, Lee EH (2012) JNK1 inhibits GluR1 expression and GluR1-mediated calcium influx through phosphorylation and stabilization of Hes-1. J Neurosci 32(5):1826–1846PubMedCrossRefGoogle Scholar
  41. 41.
    Salama-Cohen P, Arevalo MA, Meier J, Grantyn R, Rodriguez-Tebar A (2005) NGF controls dendrite development in hippocampal neurons by binding to p75NTR and modulating the cellular targets of Notch. Mol Biol Cell 16(1):339–347PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Salama-Cohen P, Arevalo MA, Grantyn R, Rodriguez-Tebar A (2006) Notch and NGF/p75NTR control dendrite morphology and the balance of excitatory/inhibitory synaptic input to hippocampal neurones through Neurogenin 3. J Neurochem 97(5):1269–1278PubMedCrossRefGoogle Scholar
  43. 43.
    Chacon PJ, Rodriguez-Tebar A (2012) Increased expression of the homologue of enhancer-of-split 1 protects neurons from beta amyloid neurotoxicity and hints at an alternative role for transforming growth factor beta1 as a neuroprotector. Alzheimers Res Ther 4(4):31PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Kong L, Hu Y, Yao Y, Jiao Y, Li S, Yang J (2015) The coumarin derivative osthole stimulates adult neural stem cells, promotes neurogenesis in the hippocampus, and ameliorates cognitive impairment in APP/PS1 transgenic mice. Biol Pharm Bull 38(9):1290–1301PubMedCrossRefGoogle Scholar
  45. 45.
    Lumsden A, Krumlauf R (1996) Patterning the vertebrate neuraxis. Science 274(5290):1109–1115PubMedCrossRefGoogle Scholar
  46. 46.
    Kiecker C, Lumsden A (2005) Compartments and their boundaries in vertebrate brain development. Nat Rev Neurosci 6(7):553–564PubMedCrossRefGoogle Scholar
  47. 47.
    Hirata H, Tomita K, Bessho Y, Kageyama R (2001) Hes1 and Hes3 regulate maintenance of the isthmic organizer and development of the mid/hindbrain. EMBO J 20(16):4454–4466PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Furukawa T, Mukherjee S, Bao ZZ, Morrow EM, Cepko CL (2000) rax, Hes1, and notch1 promote the formation of Muller glia by postnatal retinal progenitor cells. Neuron 26(2):383–394PubMedCrossRefGoogle Scholar
  49. 49.
    Sugimori M, Nagao M, Bertrand N, Parras CM, Guillemot F, Nakafuku M (2007) Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord. Development 134(8):1617–1629PubMedCrossRefGoogle Scholar
  50. 50.
    Wu Y, Liu Y, Levine EM, Rao MS (2003) Hes1 but not Hes5 regulates an astrocyte versus oligodendrocyte fate choice in glial restricted precursors. Dev Dyn 226(4):675–689PubMedCrossRefGoogle Scholar
  51. 51.
    Tanigaki K, Nogaki F, Takahashi J, Tashiro K, Kurooka H, Honjo T (2001) Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate. Neuron 29(1):45–55PubMedCrossRefGoogle Scholar
  52. 52.
    Yao J, Zheng K, Li C, Liu H, Shan X (2015) Interference of Notch1 inhibits the growth of glioma cancer cells by inducing cell autophagy and down-regulation of Notch1-Hes-1 signaling pathway. Med Oncol 32(6):610PubMedCrossRefGoogle Scholar
  53. 53.
    Kageyama R, Nakanishi S (1997) Helix-loop-helix factors in growth and differentiation of the vertebrate nervous system. Curr Opin Genet Dev 7(5):659–665PubMedCrossRefGoogle Scholar
  54. 54.
    Takebayashi K, Sasai Y, Sakai Y, Watanabe T, Nakanishi S, Kageyama R (1994) Structure, chromosomal locus, and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-1. Negative autoregulation through the multiple N box elements. J Biol Chem 269(7):5150–5156PubMedGoogle Scholar
  55. 55.
    Sasai Y, Kageyama R, Tagawa Y, Shigemoto R, Nakanishi S (1992) Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev 6(12B):2620–2634PubMedCrossRefGoogle Scholar
  56. 56.
    Kageyama R, Ohtsuka T, Tomita K (2000) The bHLH gene Hes1 regulates differentiation of multiple cell types. Mol Cells 10(1):1–7PubMedCrossRefGoogle Scholar
  57. 57.
    Davis RL, Turner DL (2001) Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning. Oncogene 20(58):8342–8357PubMedCrossRefGoogle Scholar
  58. 58.
    Ohsako S, Hyer J, Panganiban G, Oliver I, Caudy M (1994) Hairy function as a DNA-binding helix-loop-helix repressor of Drosophila sensory organ formation. Genes Dev 8(22):2743–2755PubMedCrossRefGoogle Scholar
  59. 59.
    Van Doren M, Bailey AM, Esnayra J, Ede K, Posakony JW (1994) Negative regulation of proneural gene activity: hairy is a direct transcriptional repressor of achaete. Genes Dev 8(22):2729–2742PubMedCrossRefGoogle Scholar
  60. 60.
    Chen H, Thiagalingam A, Chopra H, Borges MW, Feder JN, Nelkin BD, Baylin SB, Ball DW (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(10):5355–5360PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Grbavec D, Lo R, Liu Y, Stifani S (1998) Transducin-like Enhancer of split 2, a mammalian homologue of Drosophila Groucho, acts as a transcriptional repressor, interacts with Hairy/Enhancer of split proteins, and is expressed during neuronal development. Eur J Biochem 258(2):339–349PubMedCrossRefGoogle Scholar
  62. 62.
    Nuthall HN, Husain J, McLarren KW, Stifani S (2002) Role for Hes1-induced phosphorylation in Groucho-mediated transcriptional repression. Mol Cell Biol 22(2):389–399PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Strom A, Castella P, Rockwood J, Wagner J, Caudy M (1997) Mediation of NGF signaling by post-translational inhibition of HES-1, a basic helix-loop-helix repressor of neuronal differentiation. Genes Dev 11(23):3168–3181PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Iso T, Sartorelli V, Poizat C, Iezzi S, Wu HY, Chung G, Kedes L, Hamamori Y (2001) HERP, a novel heterodimer partner of HES/E(spl) in Notch signaling. Mol Cell Biol 21(17):6080–6089PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Hirata H, Yoshiura S, Ohtsuka T, Bessho Y, Harada T, Yoshikawa K, Kageyama R (2002) Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science 298(5594):840–843PubMedCrossRefGoogle Scholar
  66. 66.
    Jogi A, Persson P, Grynfeld A, Pahlman S, Axelson H (2002) Modulation of basic helix-loop-helix transcription complex formation by Id proteins during neuronal differentiation. J Biol Chem 277(11):9118–9126PubMedCrossRefGoogle Scholar
  67. 67.
    Bai G, Sheng N, Xie Z, Bian W, Yokota Y, Benezra R, Kageyama R, Guillemot F, Jing N (2007) Id sustains Hes1 expression to inhibit precocious neurogenesis by releasing negative autoregulation of Hes1. Dev Cell 13(2):283–297PubMedCrossRefGoogle Scholar
  68. 68.
    Bae S, Bessho Y, Hojo M, Kageyama R (2000) The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation. Development 127(13):2933–2943PubMedGoogle Scholar
  69. 69.
    Gratton MO, Torban E, Jasmin SB, Theriault FM, German MS, Stifani S (2003) Hes6 promotes cortical neurogenesis and inhibits Hes1 transcription repression activity by multiple mechanisms. Mol Cell Biol 23(19):6922–6935PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Ross SE, Greenberg ME, Stiles CD (2003) Basic helix-loop-helix factors in cortical development. Neuron 39(1):13–25PubMedCrossRefGoogle Scholar
  71. 71.
    Shimojo H, Ohtsuka T, Kageyama R (2008) Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58(1):52–64PubMedCrossRefGoogle Scholar
  72. 72.
    Bonev B, Stanley P, Papalopulu N (2012) MicroRNA-9 modulates Hes1 ultradian oscillations by forming a double-negative feedback loop. Cell Rep 2(1):10–18PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Tan SL, Ohtsuka T, Gonzalez A, Kageyama R (2012) MicroRNA9 regulates neural stem cell differentiation by controlling Hes1 expression dynamics in the developing brain. Genes Cells 17(12):952–961PubMedCrossRefGoogle Scholar
  74. 74.
    Matter-Sadzinski L, Puzianowska-Kuznicka M, Hernandez J, Ballivet M, Matter JM (2005) A bHLH transcriptional network regulating the specification of retinal ganglion cells. Development 132(17):3907–3921PubMedCrossRefGoogle Scholar
  75. 75.
    Cepko C (2014) Intrinsically different retinal progenitor cells produce specific types of progeny. Nat Rev Neurosci 15(9):615–627PubMedCrossRefGoogle Scholar
  76. 76.
    Matter-Sadzinski L, Matter JM, Ong MT, Hernandez J, Ballivet M (2001) Specification of neurotransmitter receptor identity in developing retina: the chick ATH5 promoter integrates the positive and negative effects of several bHLH proteins. Development 128(2):217–231PubMedGoogle Scholar
  77. 77.
    Skowronska-Krawczyk D, Ballivet M, Dynlacht BD, Matter JM (2004) Highly specific interactions between bHLH transcription factors and chromatin during retina development. Development 131(18):4447–4454PubMedCrossRefGoogle Scholar
  78. 78.
    Jacobsen KX, Vanderluit JL, Slack RS, Albert PR (2008) HES1 regulates 5-HT1A receptor gene transcription at a functional polymorphism: essential role in developmental expression. Mol Cell Neurosci 38(3):349–358PubMedCrossRefGoogle Scholar
  79. 79.
    Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, Sequeira A, Kushwaha N, Morris SJ, Basak A, Ou XM, Albert PR (2003) Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 23(25):8788–8799PubMedGoogle Scholar
  80. 80.
    Kinameri E, Inoue T, Aruga J, Imayoshi I, Kageyama R, Shimogori T, Moore AW (2008) Prdm proto-oncogene transcription factor family expression and interaction with the Notch-Hes pathway in mouse neurogenesis. PLoS One 3(12):e3859PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Castella P, Sawai S, Nakao K, Wagner JA, Caudy M (2000) HES-1 repression of differentiation and proliferation in PC12 cells: role for the helix 3-helix 4 domain in transcription repression. Mol Cell Biol 20(16):6170–6183PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Murata K, Hattori M, Hirai N, Shinozuka Y, Hirata H, Kageyama R, Sakai T, Minato N (2005) Hes1 directly controls cell proliferation through the transcriptional repression of p27Kip1. Mol Cell Biol 25(10):4262–4271PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Indulekha CL, Divya TS, Divya MS, Sanalkumar R, Rasheed VA, Dhanesh SB, Sebin A, George A, James J (2012) Hes-1 regulates the excitatory fate of neural progenitors through modulation of Tlx3 (HOX11L2) expression. Cell Mol Life Sci 69(4):611–627PubMedCrossRefGoogle Scholar
  84. 84.
    Jouve C, Palmeirim I, Henrique D, Beckers J, Gossler A, Ish-Horowicz D, Pourquie O (2000) Notch signalling is required for cyclic expression of the hairy-like gene HES1 in the presomitic mesoderm. Development 127(7):1421–1429PubMedGoogle Scholar
  85. 85.
    Masamizu Y, Ohtsuka T, Takashima Y, Nagahara H, Takenaka Y, Yoshikawa K, Okamura H, Kageyama R (2006) Real-time imaging of the somite segmentation clock: revelation of unstable oscillators in the individual presomitic mesoderm cells. Proc Natl Acad Sci USA 103(5):1313–1318PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Shimojo H, Isomura A, Ohtsuka T, Kori H, Miyachi H, Kageyama R (2016) Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis. Genes Dev 30(1):102–116PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Castro DS, Skowronska-Krawczyk D, Armant O, Donaldson IJ, Parras C, Hunt C, Critchley JA, Nguyen L, Gossler A, Gottgens B, Matter JM, Guillemot F (2006) Proneural bHLH and Brn proteins coregulate a neurogenic program through cooperative binding to a conserved DNA motif. Dev Cell 11(6):831–844PubMedCrossRefGoogle Scholar
  88. 88.
    Strom A, Arai N, Leers J, Gustafsson JA (2000) The Hairy and Enhancer of Split homologue-1 (HES-1) mediates the proliferative effect of 17beta-estradiol on breast cancer cell lines. Oncogene 19(51):5951–5953PubMedCrossRefGoogle Scholar
  89. 89.
    Kobayashi T, Kageyama R (2011) Hes1 oscillations contribute to heterogeneous differentiation responses in embryonic stem cells. Genes (Basel) 2(1):219–228Google Scholar
  90. 90.
    Kobayashi T, Mizuno H, Imayoshi I, Furusawa C, Shirahige K, Kageyama R (2009) The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells. Genes Dev 23(16):1870–1875PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Yoshiura S, Ohtsuka T, Takenaka Y, Nagahara H, Yoshikawa K, Kageyama R (2007) Ultradian oscillations of Stat, Smad, and Hes1 expression in response to serum. Proc Natl Acad Sci USA 104(27):11292–11297PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Ventre S, Indrieri A, Fracassi C, Franco B, Conte I, Cardone L, di Bernardo D (2015) Metabolic regulation of the ultradian oscillator Hes1 by reactive oxygen species. J Mol Biol 427(10):1887–1902PubMedCrossRefGoogle Scholar
  93. 93.
    Li S, Liu Y, Liu Z, Wang R (2016) Neural fate decisions mediated by combinatorial regulation of Hes1 and miR-9. J Biol Phys 42(1):53–68PubMedCrossRefGoogle Scholar
  94. 94.
    Leucht C, Stigloher C, Wizenmann A, Klafke R, Folchert A, Bally-Cuif L (2008) MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundary. Nat Neurosci 11(6):641–648PubMedCrossRefGoogle Scholar
  95. 95.
    Bonev B, Pisco A, Papalopulu N (2011) MicroRNA-9 reveals regional diversity of neural progenitors along the anterior-posterior axis. Dev Cell 20(1):19–32PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Dajas-Bailador F, Bonev B, Garcez P, Stanley P, Guillemot F, Papalopulu N (2012) microRNA-9 regulates axon extension and branching by targeting Map1b in mouse cortical neurons. Nat Neurosci 15:697–699CrossRefGoogle Scholar
  97. 97.
    Gaiano N, Fishell G (2002) The role of notch in promoting glial and neural stem cell fates. Ann Rev Neurosci 25:471–490PubMedCrossRefGoogle Scholar
  98. 98.
    Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A (1995) Signalling downstream of activated mammalian Notch. Nature 377(6547):355–358. doi: 10.1038/377355a0 PubMedCrossRefGoogle Scholar
  99. 99.
    Selkoe D, Kopan R (2003) Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Ann Rev Neurosci 26:565–597PubMedCrossRefGoogle Scholar
  100. 100.
    Honjo T (1996) The shortest path from the surface to the nucleus: RBP-J kappa/Su(H) transcription factor. Genes Cells 1(1):1–9PubMedCrossRefGoogle Scholar
  101. 101.
    Mason HA, Rakowiecki SM, Raftopoulou M, Nery S, Huang Y, Gridley T, Fishell G (2005) Notch signaling coordinates the patterning of striatal compartments. Development 132(19):4247–4258PubMedCrossRefGoogle Scholar
  102. 102.
    Hatakeyama J, Kageyama R (2006) Notch1 expression is spatiotemporally correlated with neurogenesis and negatively regulated by Notch1-independent Hes genes in the developing nervous system. Cereb Cortex 16(Suppl 1):i132–i137PubMedCrossRefGoogle Scholar
  103. 103.
    Sanalkumar R, Indulekha CL, Divya TS, Divya MS, Anto RJ, Vinod B, Vidyanand S, Jagatha B, Venugopal S, James J (2010) ATF2 maintains a subset of neural progenitors through CBF1/Notch independent Hes-1 expression and synergistically activates the expression of Hes-1 in Notch-dependent neural progenitors. J Neurochem 113(4):807–818PubMedCrossRefGoogle Scholar
  104. 104.
    Tomita K, Ishibashi M, Nakahara K, Ang SL, Nakanishi S, Guillemot F, Kageyama R (1996) Mammalian hairy and Enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis. Neuron 16(4):723–734PubMedCrossRefGoogle Scholar
  105. 105.
    Sanalkumar R, Dhanesh SB, James J (2010) Non-canonical activation of Notch signaling/target genes in vertebrates. Cell Mol Life Sci 67(17):2957–2968PubMedCrossRefGoogle Scholar
  106. 106.
    Zeng C, Xing R, Liu J, Xing F (2016) Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis. Apoptosis 21(1):1–12PubMedCrossRefGoogle Scholar
  107. 107.
    Borggrefe T, Lauth M, Zwijsen A, Huylebroeck D, Oswald F, Giaimo BD (2016) The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFbeta/BMP and hypoxia pathways. Biochim Biophys Acta 1863(2):303–313PubMedCrossRefGoogle Scholar
  108. 108.
    Ikawa T, Kawamoto H, Goldrath AW, Murre C (2006) E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment. J Exp Med 203(5):1329–1342PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Tanigaki K, Tsuji M, Yamamoto N, Han H, Tsukada J, Inoue H, Kubo M, Honjo T (2004) Regulation of alphabeta/gammadelta T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling. Immunity 20(5):611–622PubMedCrossRefGoogle Scholar
  110. 110.
    Curry CL, Reed LL, Nickoloff BJ, Miele L, Foreman KE (2006) Notch-independent regulation of Hes-1 expression by c-Jun N-terminal kinase signaling in human endothelial cells. Lab Invest 86(8):842–852PubMedGoogle Scholar
  111. 111.
    Ingram WJ, McCue KI, Tran TH, Hallahan AR, Wainwright BJ (2008) Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling. Oncogene 27(10):1489–1500PubMedCrossRefGoogle Scholar
  112. 112.
    Liu ZH, Dai XM, Du B (2015) Hes1: a key role in stemness, metastasis and multidrug resistance. Cancer Biol Ther 16(3):353–359PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Stockhausen MT, Sjolund J, Axelson H (2005) Regulation of the Notch target gene Hes-1 by TGFalpha induced Ras/MAPK signaling in human neuroblastoma cells. Exp Cell Res 310(1):218–228PubMedCrossRefGoogle Scholar
  114. 114.
    Sato T, Shimazaki T, Naka H, Fukami S, Satoh Y, Okano H, Lax I, Schlessinger J, Gotoh N (2010) FRS2alpha regulates Erk levels to control a self-renewal target Hes1 and proliferation of FGF-responsive neural stem/progenitor cells. Stem Cells 28(9):1661–1673PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Dave RK, Ellis T, Toumpas MC, Robson JP, Julian E, Adolphe C, Bartlett PF, Cooper HM, Reynolds BA, Wainwright BJ (2011) Sonic hedgehog and notch signaling can cooperate to regulate neurogenic divisions of neocortical progenitors. PLoS One 6(2):e14680PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Zhang SS, Liu MG, Kano A, Zhang C, Fu XY, Barnstable CJ (2005) STAT3 activation in response to growth factors or cytokines participates in retina precursor proliferation. Exp Eye Res 81(1):103–115PubMedCrossRefGoogle Scholar
  117. 117.
    Hashimoto T, Zhang XM, Chen BY, Yang XJ (2006) VEGF activates divergent intracellular signaling components to regulate retinal progenitor cell proliferation and neuronal differentiation. Development 133(11):2201–2210PubMedCrossRefGoogle Scholar
  118. 118.
    Wall DS, Mears AJ, McNeill B, Mazerolle C, Thurig S, Wang Y, Kageyama R, Wallace VA (2009) Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity. J Cell Biol 184(1):101–112PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Issack PS, Ziff EB (1998) Genetic elements regulating HES-1 induction in Wnt-1-transformed PC12 cells. Cell Growth Differ 9(10):827–836PubMedGoogle Scholar
  120. 120.
    Thisse B, Thisse C (2005) Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol 287(2):390–402PubMedCrossRefGoogle Scholar
  121. 121.
    Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10(2):116–129PubMedCrossRefGoogle Scholar
  122. 122.
    Woodbury ME, Ikezu T (2014) Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration. J Neuroimmune Pharmacol 9(2):92–101PubMedCrossRefGoogle Scholar
  123. 123.
    Li X, Wang C, Xiao J, McKeehan WL, Wang F (2016) Fibroblast growth factors, old kids on the new block. Semin Cell Dev Biol. doi: 10.1016/j.semcdb.2015.12.014 Google Scholar
  124. 124.
    Lahti L, Saarimaki-Vire J, Rita H, Partanen J (2011) FGF signaling gradient maintains symmetrical proliferative divisions of midbrain neuronal progenitors. Dev Biol 349(2):270–282PubMedCrossRefGoogle Scholar
  125. 125.
    Saarimaki-Vire J, Peltopuro P, Lahti L, Naserke T, Blak AA, Vogt Weisenhorn DM, Yu K, Ornitz DM, Wurst W, Partanen J (2007) Fibroblast growth factor receptors cooperate to regulate neural progenitor properties in the developing midbrain and hindbrain. J Neurosci 27(32):8581–8592PubMedCrossRefGoogle Scholar
  126. 126.
    Ogata T, Ueno T, Hoshikawa S, Ito J, Okazaki R, Hayakawa K, Morioka K, Yamamoto S, Nakamura K, Tanaka S, Akai M (2011) Hes1 functions downstream of growth factors to maintain oligodendrocyte lineage cells in the early progenitor stage. Neuroscience 176:132–141PubMedCrossRefGoogle Scholar
  127. 127.
    Yaar M, Zhai S, Pilch PF, Doyle SM, Eisenhauer PB, Fine RE, Gilchrest BA (1997) Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer’s disease. J Clin Invest 100(9):2333–2340PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Yaar M, Zhai S, Fine RE, Eisenhauer PB, Arble BL, Stewart KB, Gilchrest BA (2002) Amyloid beta binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J Biol Chem 277(10):7720–7725PubMedCrossRefGoogle Scholar
  129. 129.
    Ichi S, Costa FF, Bischof JM, Nakazaki H, Shen YW, Boshnjaku V, Sharma S, Mania-Farnell B, McLone DG, Tomita T, Soares MB, Mayanil CS (2010) Folic acid remodels chromatin on Hes1 and Neurog2 promoters during caudal neural tube development. J Biol Chem 285(47):36922–36932PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Zhang X, Huang G, Liu H, Chang H, Wilson JX (2012) Folic acid enhances Notch signaling, hippocampal neurogenesis, and cognitive function in a rat model of cerebral ischemia. Nutr Neurosci 15(2):55–61PubMedCrossRefGoogle Scholar
  131. 131.
    Nakazaki H, Reddy AC, Mania-Farnell BL, Shen YW, Ichi S, McCabe C, George D, McLone DG, Tomita T, Mayanil CS (2008) Key basic helix-loop-helix transcription factor genes Hes1 and Ngn2 are regulated by Pax3 during mouse embryonic development. Dev Biol 316(2):510–523PubMedCrossRefGoogle Scholar
  132. 132.
    Ichi S, Boshnjaku V, Shen YW, Mania-Farnell B, Ahlgren S, Sapru S, Mansukhani N, McLone DG, Tomita T, Mayanil CS (2011) Role of Pax3 acetylation in the regulation of Hes1 and Neurog2. Mol Biol Cell 22(4):503–512PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Hodge RD, Kahoud RJ, Hevner RF (2012) Transcriptional control of glutamatergic differentiation during adult neurogenesis. Cell Mol Life Sci 69(13):2125–2134PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Hsieh J (2012) Orchestrating transcriptional control of adult neurogenesis. Genes Dev 26(10):1010–1021PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Christie KJ, Emery B, Denham M, Bujalka H, Cate HS, Turnley AM (2013) Transcriptional regulation and specification of neural stem cells. Adv Exp Med Biol 786:129–155PubMedCrossRefGoogle Scholar
  136. 136.
    Beckervordersandforth R, Zhang CL, Lie DC (2015) Transcription-factor-dependent control of adult hippocampal neurogenesis. Cold Spring Harb Perspect Biol 7(10):a018879PubMedCrossRefGoogle Scholar
  137. 137.
    Ahmed S, Gan HT, Lam CS, Poonepalli A, Ramasamy S, Tay Y, Tham M, Yu YH (2009) Transcription factors and neural stem cell self-renewal, growth and differentiation. Cell Adh Migr 3(4):412–424PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Bray S, Furriols M (2001) Notch pathway: making sense of suppressor of hairless. Curr Biol 11(6):R217–R221PubMedCrossRefGoogle Scholar
  139. 139.
    Kovall RA (2008) More complicated than it looks: assembly of Notch pathway transcription complexes. Oncogene 27(38):5099–5109PubMedCrossRefGoogle Scholar
  140. 140.
    Shimizu T, Kagawa T, Inoue T, Nonaka A, Takada S, Aburatani H, Taga T (2008) Stabilized beta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells. Mol Cell Biol 28(24):7427–7441PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Chou SJ, O’Leary DD (2013) Role for Lhx2 in corticogenesis through regulation of progenitor differentiation. Mol Cell Neurosci 56:1–9PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Bulchand S, Grove EA, Porter FD, Tole S (2001) LIM-homeodomain gene Lhx2 regulates the formation of the cortical hem. Mech Dev 100(2):165–175PubMedCrossRefGoogle Scholar
  143. 143.
    Chou SJ, Perez-Garcia CG, Kroll TT, O’Leary DD (2009) Lhx2 specifies regional fate in Emx1 lineage of telencephalic progenitors generating cerebral cortex. Nat Neurosci 12(11):1381–1389PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    de Melo J, Zibetti C, Clark BS, Hwang W, Miranda-Angulo AL, Qian J, Blackshaw S (2016) Lhx2 is an essential factor for retinal gliogenesis and Notch signaling. J Neurosci 36(8):2391–2405PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Borrell V, Cardenas A, Ciceri G, Galceran J, Flames N, Pla R, Nobrega-Pereira S, Garcia-Frigola C, Peregrin S, Zhao Z, Ma L, Tessier-Lavigne M, Marin O (2012) Slit/Robo signaling modulates the proliferation of central nervous system progenitors. Neuron 76(2):338–352PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Kidd T, Brose K, Mitchell KJ, Fetter RD, Tessier-Lavigne M, Goodman CS, Tear G (1998) Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92(2):205–215PubMedCrossRefGoogle Scholar
  147. 147.
    Bashaw GJ, Kidd T, Murray D, Pawson T, Goodman CS (2000) Repulsive axon guidance: Abelson and Enabled play opposing roles downstream of the roundabout receptor. Cell 101(7):703–715PubMedCrossRefGoogle Scholar
  148. 148.
    Gordon WR, Arnett KL, Blacklow SC (2008) The molecular logic of Notch signaling—a structural and biochemical perspective. J Cell Sci 121(Pt 19):3109–3119PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Shu T, Butz KG, Plachez C, Gronostajski RM, Richards LJ (2003) Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice. J Neurosci 23(1):203–212PubMedGoogle Scholar
  150. 150.
    Deneen B, Ho R, Lukaszewicz A, Hochstim CJ, Gronostajski RM, Anderson DJ (2006) The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52(6):953–968PubMedCrossRefGoogle Scholar
  151. 151.
    Piper M, Barry G, Hawkins J, Mason S, Lindwall C, Little E, Sarkar A, Smith AG, Moldrich RX, Boyle GM, Tole S, Gronostajski RM, Bailey TL, Richards LJ (2010) NFIA controls telencephalic progenitor cell differentiation through repression of the Notch effector Hes1. J Neurosci 30(27):9127–9139PubMedCrossRefGoogle Scholar
  152. 152.
    Kobayashi A, Senzaki K, Ozaki S, Yoshikawa M, Shiga T (2012) Runx1 promotes neuronal differentiation in dorsal root ganglion. Mol Cell Neurosci 49(1):23–31PubMedCrossRefGoogle Scholar
  153. 153.
    Leem YE, Choi HK, Jung SY, Kim BJ, Lee KY, Yoon K, Qin J, Kang JS, Kim ST (2011) Esco2 promotes neuronal differentiation by repressing Notch signaling. Cell Signal 23(11):1876–1884PubMedCrossRefGoogle Scholar
  154. 154.
    Jalali A, Bassuk AG, Kan L, Israsena N, Mukhopadhyay A, McGuire T, Kessler JA (2011) HeyL promotes neuronal differentiation of neural progenitor cells. J Neurosci Res 89(3):299–309PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Kawahara H, Imai T, Okano H (2012) micrornas in neural stem cells and neurogenesis. Front Neurosci 6:30PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Lang MF, Shi Y (2012) Dynamic roles of microRNAs in neurogenesis. Front Neurosci 6:71PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Davis GM, Haas MA, Pocock R (2015) MicroRNAs: not “Fine-Tuners” but key regulators of neuronal development and function. Front Neurol 6:245PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Basak I, Patil KS, Alves G, Larsen JP, Moller SG (2016) microRNAs as neuroregulators, biomarkers and therapeutic agents in neurodegenerative diseases. Cell Mol Life Sci 73(4):811–827PubMedCrossRefGoogle Scholar
  159. 159.
    De Pietri Tonelli D, Pulvers JN, Haffner C, Murchison EP, Hannon GJ, Huttner WB (2008) miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex. Development 135(23):3911–3921CrossRefGoogle Scholar
  160. 160.
    Wienholds E, Kloosterman WP, Miska E, Alvarez-Saavedra E, Berezikov E, de Bruijn E, Horvitz HR, Kauppinen S, Plasterk RH (2005) MicroRNA expression in zebrafish embryonic development. Science 309(5732):310–311PubMedCrossRefGoogle Scholar
  161. 161.
    Shibata M, Nakao H, Kiyonari H, Abe T, Aizawa S (2011) MicroRNA-9 regulates neurogenesis in mouse telencephalon by targeting multiple transcription factors. J Neurosci 31(9):3407–3422PubMedCrossRefGoogle Scholar
  162. 162.
    Wang C, Yao N, Lu CL, Li D, Ma X (2010) Mouse microRNA-124 regulates the expression of Hes1 in P19 cells. Front Biosci (Elite Ed) 2:127–132Google Scholar
  163. 163.
    Papagiannakopoulos T, Kosik KS (2009) MicroRNA-124: micromanager of neurogenesis. Cell Stem Cell 4(5):375–376PubMedCrossRefGoogle Scholar
  164. 164.
    Garzia L, Andolfo I, Cusanelli E, Marino N, Petrosino G, De Martino D, Esposito V, Galeone A, Navas L, Esposito S, Gargiulo S, Fattet S, Donofrio V, Cinalli G, Brunetti A, Vecchio LD, Northcott PA, Delattre O, Taylor MD, Iolascon A, Zollo M (2009) MicroRNA-199b-5p impairs cancer stem cells through negative regulation of HES1 in medulloblastoma. PLoS One 4(3):e4998PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Chen L, Zhang W, Yan W, Han L, Zhang K, Shi Z, Zhang J, Wang Y, Li Y, Yu S, Pu P, Jiang C, Jiang T, Kang C (2012) The putative tumor suppressor miR-524-5p directly targets Jagged-1 and Hes-1 in glioma. Carcinogenesis 33(11):2276–2282PubMedCrossRefGoogle Scholar
  166. 166.
    Whitmarsh AJ, Davis RJ (2000) Regulation of transcription factor function by phosphorylation. Cell Mol Life Sci 57(8–9):1172–1183PubMedCrossRefGoogle Scholar
  167. 167.
    Todi SV, Paulson HL (2011) Balancing act: deubiquitinating enzymes in the nervous system. Trends Neurosci 34(7):370–382PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Komander D, Rape M (2012) The ubiquitin code. Ann Rev Biochem 81:203–229PubMedCrossRefGoogle Scholar
  169. 169.
    Chen G, Courey AJ (2000) Groucho/TLE family proteins and transcriptional repression. Gene 249(1–2):1–16PubMedCrossRefGoogle Scholar
  170. 170.
    Kobayashi T, Iwamoto Y, Takashima K, Isomura A, Kosodo Y, Kawakami K, Nishioka T, Kaibuchi K, Kageyama R (2015) Deubiquitinating enzymes regulate Hes1 stability and neuronal differentiation. FEBS J 282(13):2411–2423PubMedCrossRefGoogle Scholar
  171. 171.
    Sui Y, Zhang Z, Guo Y, Sun Y, Zhang X, Xie C, Li Y, Xi G (2009) The function of Notch1 signaling was increased in parallel with neurogenesis in rat hippocampus after chronic fluoxetine administration. Biol Pharm Bull 32(10):1776–1782PubMedCrossRefGoogle Scholar
  172. 172.
    Cabras S, Saba F, Reali C, Scorciapino ML, Sirigu A, Talani G, Biggio G, Sogos V (2010) Antidepressant imipramine induces human astrocytes to differentiate into cells with neuronal phenotype. Int J Neuropsychopharmacol 13(5):603–615PubMedCrossRefGoogle Scholar
  173. 173.
    Chen J, Zacharek A, Li A, Cui X, Roberts C, Lu M, Chopp M (2008) Atorvastatin promotes presenilin-1 expression and Notch1 activity and increases neural progenitor cell proliferation after stroke. Stroke 39(1):220–226PubMedCrossRefGoogle Scholar
  174. 174.
    Yang R, Yi L, Dong Z, Ouyang Q, Zhou J, Pang Y, Wu Y, Xu L, Cui H (2016) Tigecycline inhibits glioma growth by regulating miRNA-199b-5p-HES1-AKT pathway. Mol Cancer 15(3):421–429CrossRefGoogle Scholar
  175. 175.
    Katakura M, Hashimoto M, Shahdat HM, Gamoh S, Okui T, Matsuzaki K, Shido O (2009) Docosahexaenoic acid promotes neuronal differentiation by regulating basic helix-loop-helix transcription factors and cell cycle in neural stem cells. Neuroscience 160(3):651–660PubMedCrossRefGoogle Scholar
  176. 176.
    Katakura M, Hashimoto M, Okui T, Shahdat HM, Matsuzaki K, Shido O (2013) Omega-3 polyunsaturated fatty acids enhance neuronal differentiation in cultured rat neural stem cells. Stem Cells Int 2013:490476PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Guo HD, Tian JX, Zhu J, Li L, Sun K, Shao SJ, Cui GH (2015) Electroacupuncture suppressed neuronal apoptosis and improved cognitive impairment in the AD model rats possibly via downregulation of notch signaling pathway. Evid Based Complement Alternat Med 2015:393569PubMedPubMedCentralGoogle Scholar
  178. 178.
    Zhang YM, Chen SX, Dai QF, Jiang ST, Chen AL, Tang CZ, Zhang YQ (2015) Effect of acupuncture on the Notch signaling pathway in rats with brain injury. Chin J Integr Med. doi: 10.1007/s11655-015-1969-9 Google Scholar
  179. 179.
    Li Y, Zhuang P, Shen B, Zhang Y, Shen J (2012) Baicalin promotes neuronal differentiation of neural stem/progenitor cells through modulating p-stat3 and bHLH family protein expression. Brain Res 1429:36–42PubMedCrossRefGoogle Scholar
  180. 180.
    Li Y, Lau WM, So KF, Tong Y, Shen J (2011) Caveolin-1 promote astroglial differentiation of neural stem/progenitor cells through modulating Notch1/NICD and Hes1 expressions. Biochem Biophys Res Commun 407(3):517–524PubMedCrossRefGoogle Scholar
  181. 181.
    Wu ZQ, Li D, Huang Y, Chen XP, Huang W, Liu CF, Zhao HQ, Xu RX, Cheng M, Schachner M, Ma QH (2016) Caspr controls the temporal specification of neural progenitor cells through notch signaling in the developing mouse cerebral cortex. Cereb Cortex. doi: 10.1093/cercor/bhv318 Google Scholar
  182. 182.
    Bansal R, You SH, Herzig CT, Zoeller RT (2005) Maternal thyroid hormone increases HES expression in the fetal rat brain: an effect mimicked by exposure to a mixture of polychlorinated biphenyls (PCBs). Brain Res Dev Brain Res 156(1):13–22PubMedCrossRefGoogle Scholar
  183. 183.
    Fusco S, Leone L, Barbati SA, Samengo D, Piacentini R, Maulucci G, Toietta G, Spinelli M, McBurney M, Pani G, Grassi C (2016) A CREB-Sirt1-Hes1 circuitry mediates neural stem cell response to glucose availability. Cell Rep 14(5):1195–1205PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Sivadasan Bindu Dhanesh
    • 1
  • Chandramohan Subashini
    • 1
  • Jackson James
    • 1
  1. 1.Neuro Stem Cell Biology Laboratory, Neurobiology DivisionRajiv Gandhi Centre for BiotechnologyThiruvananthapuramIndia

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