Abstract
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.
Abbreviations
- Hes:
-
Hairy and enhancer of split
- BLBP:
-
Brain lipid-binding protein
- NICD:
-
Notch intracellular domain
- RBP-Jκ:
-
Recombination signal binding protein for immunoglobulin kappa J region
- DAPT:
-
N-[N-(3,5-difluoro-phenacetyl-l-alanyl]-S-phenylglycine tert-butyl ester
- FGF:
-
Fibroblast growth factor
- JNK:
-
C-Jun N-terminal kinase
- ATF2:
-
Activating transcription factor 2
- EGF:
-
Epidermal growth factor
- MAPK:
-
Mitogen-activated protein kinase
- ERK:
-
Extracellular signal-regulated kinases
- Shh:
-
Sonic hedgehog
- AP1:
-
Activator protein 1
- bHLH:
-
Basic helix-loop-helix
- Ngn:
-
Neurogenin
- ES cells:
-
Embryonic stem cells
- BMP:
-
Bone morphogenetic protein
- LIF:
-
Leukemia inhibitory factor
- Jak:
-
Janus kinase
- ROS:
-
Reactive oxygen species
- 5-HT1A:
-
5-Hydroxytryptamine
- Tlx3:
-
T-cell leukemia homeobox protein 3
- CDK:
-
Cyclin-dependent kinase
- GABA:
-
Gamma-aminobutyric acid
- miRNA:
-
microRNA
- PDGF:
-
Platelet-derived growth factor
- VEGF:
-
Vascular endothelial growth factor
- RGC:
-
Retinal ganglion cell
- STATs:
-
Signal transducer and activator of transcription
- CNTF:
-
Ciliary neurotrophic factor
- NGF:
-
Nerve growth factor
- TGFβ1:
-
Transforming growth factor beta 1
- Aβ:
-
Amyloid beta
- DNMT:
-
DNA methyltransferase
- DRG:
-
Dorsal root ganglion
- Pax3:
-
Paired box 3
- PI3K:
-
Phosphatidylinositol 3 kinase
- Lhx2:
-
LIM homeobox 2
- VZ:
-
Ventricular zone
- SVZ:
-
Subventricular zone
- CAT:
-
Chloramphenicol acetyltransferase
- TLE:
-
Transducin-like enhancer of split
- NFIA:
-
Nuclear factor IA
- LNA:
-
Locked nucleic acid
- Camk2δ:
-
Ca2+/calmodulin-dependent protein kinase II delta
- PARP-1:
-
Poly [ADP-ribose] polymerase 1
- PKC:
-
Protein kinase C
- DUBs:
-
Deubiquitinating enzymes
- PS1:
-
Presenilin
- DHA:
-
Docosahexaenoic acid
- EPA:
-
Eicosapentaenoic acid
- MAP2:
-
Microtubule-associated protein 2
- GFAP:
-
Glial fibrillary acidic protein
- S100β:
-
S100 calcium-binding protein Β
- CGNs:
-
Cerebellar granule neurons
- AMPA:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
- AD:
-
Alzheimer’s disease
- ZLI:
-
Zona limitans intrathalamica
- CNS:
-
Central nervous system
- PNS:
-
Peripheral nervous system
- NEP:
-
Neuroepithelial progenitors
- Id:
-
Inhibitors of differentiation
- NPC:
-
Neural progenitor cell
References
Schuurmans C, Guillemot F (2002) Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr Opin Neurobiol 12(1):26–34
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):223–233
Guillemot F (2007) Spatial and temporal specification of neural fates by transcription factor codes. Development 134(21):3771–3780
Wen S, Li H, Liu J (2009) Dynamic signaling for neural stem cell fate determination. Cell Adh Migr 3(1):107–117
Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD (2007) Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci 8(6):427–437
Guillemot F (2007) Cell fate specification in the mammalian telencephalon. Prog Neurobiol 83(1):37–52
Ohnuma S, Philpott A, Harris WA (2001) Cell cycle and cell fate in the nervous system. Curr Opin Neurobiol 11(1):66–73
Cremisi F, Philpott A, Ohnuma S (2003) Cell cycle and cell fate interactions in neural development. Curr Opin Neurobiol 13(1):26–33
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):648–657
Zhong W, Chia W (2008) Neurogenesis and asymmetric cell division. Curr Opin Neurobiol 18(1):4–11
Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770–776
Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137(2):216–233
Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138(17):3593–3612
Pierfelice T, Alberi L, Gaiano N (2011) Notch in the vertebrate nervous system: an old dog with new tricks. Neuron 69(5):840–855
Kageyama R, Ohtsuka T (1999) The Notch-Hes pathway in mammalian neural development. Cell Res 9(3):179–188
Borggrefe T, Oswald F (2009) The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 66(10):1631–1646
Iso T, Kedes L, Hamamori Y (2003) HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194(3):237–255
Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7(9):678–689
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):4583–4596
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):3136–3148
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):283–293
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):30467–30474
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):2196–2207
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):2467–2476
Kageyama R, Ohtsuka T, Kobayashi T (2008) Roles of Hes genes in neural development. Dev Growth Differ 50(Suppl 1):S97–S103
Kageyama R, Ohtsuka T, Kobayashi T (2007) The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development 134(7):1243–1251
Shimojo H, Ohtsuka T, Kageyama R (2011) Dynamic expression of notch signaling genes in neural stem/progenitor cells. Front Neurosci 5:78
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 34:85–90
Kobayashi T, Kageyama R (2014) Expression dynamics and functions of Hes factors in development and diseases. Curr Top Dev Biol 110:263–283
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):5539–5550
Takatsuka K, Hatakeyama J, Bessho Y, Kageyama R (2004) Roles of the bHLH gene Hes1 in retinal morphogenesis. Brain Res 1004(1–2):148–155
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):464–478
Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R (2005) Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res 306(2):343–348
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):12413–12425
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):1207–1216
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):3465–3476
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):1799–1805
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):645–659
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):815–829
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):1826–1846
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):339–347
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):1269–1278
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):31
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):1290–1301
Lumsden A, Krumlauf R (1996) Patterning the vertebrate neuraxis. Science 274(5290):1109–1115
Kiecker C, Lumsden A (2005) Compartments and their boundaries in vertebrate brain development. Nat Rev Neurosci 6(7):553–564
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):4454–4466
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):383–394
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):1617–1629
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):675–689
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):45–55
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):610
Kageyama R, Nakanishi S (1997) Helix-loop-helix factors in growth and differentiation of the vertebrate nervous system. Curr Opin Genet Dev 7(5):659–665
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):5150–5156
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):2620–2634
Kageyama R, Ohtsuka T, Tomita K (2000) The bHLH gene Hes1 regulates differentiation of multiple cell types. Mol Cells 10(1):1–7
Davis RL, Turner DL (2001) Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning. Oncogene 20(58):8342–8357
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):2743–2755
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):2729–2742
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):5355–5360
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):339–349
Nuthall HN, Husain J, McLarren KW, Stifani S (2002) Role for Hes1-induced phosphorylation in Groucho-mediated transcriptional repression. Mol Cell Biol 22(2):389–399
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):3168–3181
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):6080–6089
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):840–843
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):9118–9126
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):283–297
Bae S, Bessho Y, Hojo M, Kageyama R (2000) The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation. Development 127(13):2933–2943
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):6922–6935
Ross SE, Greenberg ME, Stiles CD (2003) Basic helix-loop-helix factors in cortical development. Neuron 39(1):13–25
Shimojo H, Ohtsuka T, Kageyama R (2008) Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58(1):52–64
Bonev B, Stanley P, Papalopulu N (2012) MicroRNA-9 modulates Hes1 ultradian oscillations by forming a double-negative feedback loop. Cell Rep 2(1):10–18
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):952–961
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):3907–3921
Cepko C (2014) Intrinsically different retinal progenitor cells produce specific types of progeny. Nat Rev Neurosci 15(9):615–627
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):217–231
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):4447–4454
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):349–358
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):8788–8799
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):e3859
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):6170–6183
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):4262–4271
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):611–627
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):1421–1429
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):1313–1318
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):102–116
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):831–844
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):5951–5953
Kobayashi T, Kageyama R (2011) Hes1 oscillations contribute to heterogeneous differentiation responses in embryonic stem cells. Genes (Basel) 2(1):219–228
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):1870–1875
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):11292–11297
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):1887–1902
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):53–68
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):641–648
Bonev B, Pisco A, Papalopulu N (2011) MicroRNA-9 reveals regional diversity of neural progenitors along the anterior-posterior axis. Dev Cell 20(1):19–32
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 15:697–699
Gaiano N, Fishell G (2002) The role of notch in promoting glial and neural stem cell fates. Ann Rev Neurosci 25:471–490
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
Selkoe D, Kopan R (2003) Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Ann Rev Neurosci 26:565–597
Honjo T (1996) The shortest path from the surface to the nucleus: RBP-J kappa/Su(H) transcription factor. Genes Cells 1(1):1–9
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):4247–4258
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–i137
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):807–818
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):723–734
Sanalkumar R, Dhanesh SB, James J (2010) Non-canonical activation of Notch signaling/target genes in vertebrates. Cell Mol Life Sci 67(17):2957–2968
Zeng C, Xing R, Liu J, Xing F (2016) Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis. Apoptosis 21(1):1–12
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):303–313
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):1329–1342
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):611–622
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):842–852
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):1489–1500
Liu ZH, Dai XM, Du B (2015) Hes1: a key role in stemness, metastasis and multidrug resistance. Cancer Biol Ther 16(3):353–359
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):218–228
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):1661–1673
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):e14680
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):103–115
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):2201–2210
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):101–112
Issack PS, Ziff EB (1998) Genetic elements regulating HES-1 induction in Wnt-1-transformed PC12 cells. Cell Growth Differ 9(10):827–836
Thisse B, Thisse C (2005) Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol 287(2):390–402
Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10(2):116–129
Woodbury ME, Ikezu T (2014) Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration. J Neuroimmune Pharmacol 9(2):92–101
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
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):270–282
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):8581–8592
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 176:132–141
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):2333–2340
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):7720–7725
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):36922–36932
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):55–61
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):510–523
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):503–512
Hodge RD, Kahoud RJ, Hevner RF (2012) Transcriptional control of glutamatergic differentiation during adult neurogenesis. Cell Mol Life Sci 69(13):2125–2134
Hsieh J (2012) Orchestrating transcriptional control of adult neurogenesis. Genes Dev 26(10):1010–1021
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 786:129–155
Beckervordersandforth R, Zhang CL, Lie DC (2015) Transcription-factor-dependent control of adult hippocampal neurogenesis. Cold Spring Harb Perspect Biol 7(10):a018879
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):412–424
Bray S, Furriols M (2001) Notch pathway: making sense of suppressor of hairless. Curr Biol 11(6):R217–R221
Kovall RA (2008) More complicated than it looks: assembly of Notch pathway transcription complexes. Oncogene 27(38):5099–5109
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):7427–7441
Chou SJ, O’Leary DD (2013) Role for Lhx2 in corticogenesis through regulation of progenitor differentiation. Mol Cell Neurosci 56:1–9
Bulchand S, Grove EA, Porter FD, Tole S (2001) LIM-homeodomain gene Lhx2 regulates the formation of the cortical hem. Mech Dev 100(2):165–175
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):1381–1389
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):2391–2405
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):338–352
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):205–215
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):703–715
Gordon WR, Arnett KL, Blacklow SC (2008) The molecular logic of Notch signaling—a structural and biochemical perspective. J Cell Sci 121(Pt 19):3109–3119
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):203–212
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):953–968
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):9127–9139
Kobayashi A, Senzaki K, Ozaki S, Yoshikawa M, Shiga T (2012) Runx1 promotes neuronal differentiation in dorsal root ganglion. Mol Cell Neurosci 49(1):23–31
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):1876–1884
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):299–309
Kawahara H, Imai T, Okano H (2012) micrornas in neural stem cells and neurogenesis. Front Neurosci 6:30
Lang MF, Shi Y (2012) Dynamic roles of microRNAs in neurogenesis. Front Neurosci 6:71
Davis GM, Haas MA, Pocock R (2015) MicroRNAs: not “Fine-Tuners” but key regulators of neuronal development and function. Front Neurol 6:245
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):811–827
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):3911–3921
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):310–311
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):3407–3422
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) 2:127–132
Papagiannakopoulos T, Kosik KS (2009) MicroRNA-124: micromanager of neurogenesis. Cell Stem Cell 4(5):375–376
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):e4998
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):2276–2282
Whitmarsh AJ, Davis RJ (2000) Regulation of transcription factor function by phosphorylation. Cell Mol Life Sci 57(8–9):1172–1183
Todi SV, Paulson HL (2011) Balancing act: deubiquitinating enzymes in the nervous system. Trends Neurosci 34(7):370–382
Komander D, Rape M (2012) The ubiquitin code. Ann Rev Biochem 81:203–229
Chen G, Courey AJ (2000) Groucho/TLE family proteins and transcriptional repression. Gene 249(1–2):1–16
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):2411–2423
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):1776–1782
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):603–615
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):220–226
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):421–429
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):651–660
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 2013:490476
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 2015:393569
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
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 1429:36–42
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):517–524
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
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):13–22
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):1195–1205
Acknowledgments
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.
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Dhanesh, S.B., Subashini, C. & James, J. Hes1: the maestro in neurogenesis. Cell. Mol. Life Sci. 73, 4019–4042 (2016). https://doi.org/10.1007/s00018-016-2277-z
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DOI: https://doi.org/10.1007/s00018-016-2277-z