Skip to main content

Dynamic expression and roles of Hes factors in neural development

Cell and Tissue Research volume 359, pages 125–133 (2015)Cite this article

Abstract

The basic helix-loop-helix factors Hes1 and Hes5 repress the expression of proneural factors such as Ascl1, thereby inhibiting neuronal differentiation and maintaining neural progenitor cells (NPCs). Hes1 expression oscillates by negative feedback with a period of about 2–3 h in proliferating NPCs. Induction of sustained expression of Hes1 in NPCs inhibits their cell-cycle progression, suggesting that the oscillatory expression of Hes1 is important for the proliferation of NPCs. Hes1 oscillation drives the oscillatory expression of proneural factors such as Ascl1 by periodic repression. By contrast, in differentiating neurons, Hes1 expression disappears and the expression of proneural factors is up-regulated and sustained. A new optogenetics approach that induces Ascl1 expression by blue light illumination demonstrated that sustained expression of Ascl1 induces neuronal differentiation, whereas oscillatory expression of Ascl1 activates the proliferation of NPCs. These results together indicate that Hes1 regulates the oscillatory versus sustained expression of the proneural factor Ascl1, which in turn regulates the proliferation of NPCs and the subsequent processes of cell-cycle exit and neuronal fate determination, depending on the expression dynamics.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  • Akazawa C, Sasai Y, Nakanishi S, Kageyama R (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

    CAS  PubMed  Google Scholar 

  • Ali F, Hindley C, McDowell G, Deibler R, Jones A, Kirschner M, Guillemot F, Philpott A (2011) Cell cycle-regulated multi-site phosphorylation of Neurogenin 2 coordinates cell cycling with differentiation during neurogenesis. Development 138:4267–4277

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Alvarez-Buylla A, Garcia-Verdugo JM, Tramontin AD (2001) A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2:287–293

    CAS  PubMed  Article  Google Scholar 

  • 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 133:2467–2476

    CAS  PubMed  Article  Google Scholar 

  • Bertrand N, Castro DS, Guillemot F (2002) Proneural genes and the specification of neural cell types. Nat Rev Neurosci 3:517–530

    CAS  PubMed  Article  Google Scholar 

  • Castro DS, Skowronska-Krawczyk D, Armant O, Donaldson IJ, Parras C, Hunt C, Critchley JA, Nguyen L, Gossler A, Gottgens B, Mtter JM, Guillemot F (2006) Proneural bHLH and Brn proteins coregulate a neurogenic program through cooperative binding to a conserved DNA motif. Dev Cell 11:831–844

    CAS  PubMed  Article  Google Scholar 

  • Fietz SA, Kelava I, Vogt J, Wilsch-Bräuninger M, Stenzel D, Fish JL, Corbeil D, Riehn A, Distler W, Nitsch R, Huttner WB (2010) OSVZ progenitors of human and ferret neocortetx are epithelial-like and expand by integrin signaling. Nat Neurosci 13:690–699

    CAS  PubMed  Article  Google Scholar 

  • Fishell G, Kriegstein AR (2003) Neurons from radial glia: the consequences of asymmetric inheritance. Curr Opin Neurobiol 13:34–41

    CAS  PubMed  Article  Google Scholar 

  • Fortini ME (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16:633–647

    CAS  PubMed  Article  Google Scholar 

  • Fujita S (2003) The discovery of the matrix cell, the identification of the multipotent neural stem cell and the development of the central nervous system. Cell Struct Funct 28:205–228

    PubMed  Article  Google Scholar 

  • Götz M, Huttner WB (2005) The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6:777–788

    PubMed  Article  Google Scholar 

  • Grbavec D, Stifani S (1996) Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif. Biochem Biophys Res Commun 223:701–705

    CAS  PubMed  Article  Google Scholar 

  • Hansen DV, Lui JH, Parker PRL, Kriegstein AR (2010) Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464:554–561

    CAS  PubMed  Article  Google Scholar 

  • 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 131:5539–5550

    CAS  PubMed  Article  Google Scholar 

  • Hindley C, Ali F, McDowell G, Cheng K, Jones A, Guillemot F, Philpott A (2012) Post-translational modification of Ngn2 differentially affects transcription of distinct targets to regulate the balance between progenitor maintenance and differentiation. Development 139:1718–1723

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Hirabayashi Y, Suzki N, Tsuboi M, Endo TA, Toyoda T, Shinga J, Koseki H, Vidal M, Gotoh Y (2009) Polycomb limits the neurogenic competence of neural precursor cells to promote astrogenic fate transition. Neuron 63:600–613

    CAS  PubMed  Article  Google Scholar 

  • 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 20:4454–4466

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • 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 298:840–843

    CAS  PubMed  Article  Google Scholar 

  • Hirata H, Bessho Y, Kokubu H, Masamizu Y, Yamada S, Lewis J, Kageyama R (2004) Instability of Hes7 protein is critical for the somite segmentation clock. Nat Genet 36:750–754

    CAS  PubMed  Article  Google Scholar 

  • Honjo T (1996) The shortest path from the surface to the nucleus: RBP-J κ/Su(H) transcription factor. Genes Cells 1:1–9

    CAS  PubMed  Article  Google Scholar 

  • Imayoshi I, Sakamoto M, Yamaguchi M, Mori K, Kageyama R (2010) Essential roles of Notch signaling in maintenance of neural stem cells in the developing and adult brains. J Neurosci 30:3489–3498

    CAS  PubMed  Article  Google Scholar 

  • Imayoshi I, Isomura A, Harima Y, Kawaguchi K, Kori H, Miyachi H, Fujiwara TK, Ishidate F, Kageyama R (2013) Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science 342:1203–1208

    CAS  PubMed  Article  Google Scholar 

  • 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 13:1799–1805

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ishibashi M, Ang S-L, 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 9:3136–3148

    CAS  PubMed  Article  Google Scholar 

  • Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A (1995) Signalling downstream of activated mammalian Notch. Nature 377:355–358

    CAS  PubMed  Article  Google Scholar 

  • Kageyama R, Ohtsuka T, Kobayashi T (2007) The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development 134:1243–1251

    CAS  PubMed  Article  Google Scholar 

  • Kageyama R, Ohtsuka T, Shimojo H, Imayoshi I (2008) Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition. Nat Neurosci 11:1247–1251

    CAS  PubMed  Article  Google Scholar 

  • Kawaguchi A, Ikawa T, Kasukawa T, Ueda HR, Kurimoto K, Saitou M, Matsuzaki F (2008) Single-cell gene profiling defines differential progenitor subclasses in mammalian neurogenesis. Development 135:3113–3124

    CAS  PubMed  Article  Google Scholar 

  • Kiecker C, Lumsden A (2005) Compartments and their boundaries in vertebrate brain development. Nat Rev Neurosci 6:553–564

    CAS  PubMed  Article  Google Scholar 

  • Knuckles P, Vogt MA, Lugert S, Milo M, Chong MM, Hautbergue GM, Wilson SA, Littman DR, Taylor V (2012) Drosha regulates neurogenesis by controlling neurogenin 2 expression independent of microRNAs. Nat Neurosci 15:962–969

    CAS  PubMed  Article  Google Scholar 

  • Kopan R, Ilagan MXG (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Malatesta P, Hartfuss E, Götz M (2000) Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127:5253–5263

    CAS  PubMed  Google Scholar 

  • 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 U S A 103:1313–1318

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Miller FD, Gauthier AS (2007) Timing is everything: making neurons versus glia in the developing cortex. Neuron 54:357–369

    CAS  PubMed  Article  Google Scholar 

  • Miyata T, Kawaguchi A, Okano H, Ogawa M (2001) Asymmetric inheritance of radial glial fibers by cortical neurons. Neuron 31:727–741

    CAS  PubMed  Article  Google Scholar 

  • Mizutani K, Yoon K, Dang L, Tokunaga A, Gaiano N (2007) Differential Notch signalling distinguishes neural stem cells from intermediate progenitors. Nature 449:351–355

    CAS  PubMed  Article  Google Scholar 

  • Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR (2001) Neurons derived from radial glial cells establish radial units in neocortex. Nature 409:714–720

    CAS  PubMed  Article  Google Scholar 

  • 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 18:2196–2207

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • 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 276:30467–30474

    CAS  PubMed  Article  Google Scholar 

  • Pierfelice T, Alberi L, Gaiano N (2011) Notch in the vertebrate nervous system: an old dog with new tricks. Neuron 69:840–855

    CAS  PubMed  Article  Google Scholar 

  • Ross SE, Greenberg ME, Stiles CD (2003) Basic helix-loop-helix factors in cortical development. Neuron 39:13–25

    CAS  PubMed  Article  Google Scholar 

  • Sang L, Coller HA, Roberts JM (2008) Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science 321:1095–1100

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • 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 6:2620–2634

    CAS  PubMed  Article  Google Scholar 

  • Sessa A, Mao C, Hadjantonakis AK, Klein WH, Broccoli V (2008) Tbr2 directs conversion of radial glia into basal precursors and guides neuronal amplification by indirect neurogenesis in the developing neocortex. Neuron 60:56–69

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Shimojo H, Ohtsuka T, Kageyama R (2008) Oscillations in Notch signaling regulate maintenance of neural progenitors. Neuron 58:52–64

    CAS  PubMed  Article  Google Scholar 

  • Shitamukai A, Konno D, Matsuzaki F (2011) Oblique radial glial divisions in the developing mouse neocortex induce self-renewing progenitors outside the germinal zone that resemble primate outer subventricular zone progenitors. J Neurosci 31:3683–3695

    CAS  PubMed  Article  Google Scholar 

  • Sriuranpong V, Borges MW, Strock CL, Nakakura EK, Watkins DN, Blaumueller CM, Nelkin BD, Ball DW (2002) Notch signaling induces rapid degradation of achaete-scute homolog 1. Mol Cell Biol 22:3129–3139

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • 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 269:5150–5156

    CAS  PubMed  Google Scholar 

  • Tan S-L, Nishi M, Ohtsuka T, Matsui T, Takemoto K, Kamio-Miura A, Aburatani H, Shinkai Y, Kageyama R (2012) Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development. Development 139:3806–3816

    CAS  PubMed  Article  Google Scholar 

  • Wang X, Chen X, Yang Y (2012) Spatiotemporal control of gene expression by a light-switchable transgene system. Nat Methods 9:266–269

    CAS  PubMed  Article  Google Scholar 

  • Wilkinson G, Dennis D, Schuurmans C (2013) Proneural genes in neocortical development. Neuroscience 253:256–273

    CAS  PubMed  Article  Google Scholar 

  • 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 U S A 104:11292–11297

    CAS  PubMed Central  PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

  1. Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, 606-8507, Japan

    Ryoichiro Kageyama, Hiromi Shimojo & Itaru Imayoshi

  2. Japan Science and Technology Agency, CREST, Shogoin-Kawahara, Sakyo-ku, Kyoto, 606-8507, Japan

    Ryoichiro Kageyama & Hiromi Shimojo

  3. World Premier International Research Initiative—Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, 606-8501, Japan

    Ryoichiro Kageyama, Hiromi Shimojo & Itaru Imayoshi

  4. The Hakubi Center, Kyoto University, Kyoto, 606-8501, Japan

    Itaru Imayoshi

Authors
  1. Ryoichiro Kageyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiromi Shimojo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Itaru Imayoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ryoichiro Kageyama.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kageyama, R., Shimojo, H. & Imayoshi, I. Dynamic expression and roles of Hes factors in neural development. Cell Tissue Res 359, 125–133 (2015). https://doi.org/10.1007/s00441-014-1888-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-014-1888-7

Keywords

  • Basic helix-loop-helix factor
  • Hes1
  • Neural progenitor cell
  • Notch signaling
  • Oscillatory expression
  • Proneural factor