Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 298 (5594): 840-843

Copyright © 2002 by the American Association for the Advancement of Science

Oscillatory Expression of the bHLH Factor Hes1 Regulated by a Negative Feedback Loop

Hiromi Hirata,1 Shigeki Yoshiura,1 Toshiyuki Ohtsuka,1* Yasumasa Bessho,1 Takahiro Harada,2 Kenichi Yoshikawa,2 Ryoichiro Kageyama1dagger

Transcription of messenger RNAs (mRNAs) for Notch signaling molecules oscillates with 2-hour cycles, and this oscillation is important for coordinated somite segmentation. However, the molecular mechanism of such oscillation remains to be determined. Here, we show that serum treatment of cultured cells induces cyclic expression of both mRNA and protein of the Notch effector Hes1, a basic helix-loop-helix (bHLH) factor, with 2-hour periodicity. Cycling is cell-autonomous and depends on negative autoregulation of hes1 transcription and ubiquitin-proteasome-mediated degradation of Hes1 protein. Because Hes1 oscillation can be seen in many cell types, this clock may regulate timing in many biological systems.

1 Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
2 Department of Physics, Graduate School of Science, Kyoto University and CREST, Kyoto 606-8502, Japan.
*   Present address: Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.

dagger    To whom correspondence should be addressed. E-mail: rkageyam{at}

Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.
J. E. Church, J. Trieu, A. Chee, T. Naim, S. M. Gehrig, S. Lamon, C. Angelini, A. P. Russell, and G. S. Lynch (2014)
Exp Physiol 99, 675-687
   Abstract »    Full Text »    PDF »
Nucleocytoplasmic Shuttling of a GATA Transcription Factor Functions as a Development Timer.
H. Cai, M. Katoh-Kurasawa, T. Muramoto, B. Santhanam, Y. Long, L. Li, M. Ueda, P. A. Iglesias, G. Shaulsky, and P. N. Devreotes (2014)
Science 343, 1249531
   Abstract »    Full Text »    PDF »
The Transcriptome of Utricle Hair Cell Regeneration in the Avian Inner Ear.
Y.-C. Ku, N. A. Renaud, R. A. Veile, C. Helms, C. C. J. Voelker, M. E. Warchol, and M. Lovett (2014)
J. Neurosci. 34, 3523-3535
   Abstract »    Full Text »    PDF »
Oscillatory Control of Factors Determining Multipotency and Fate in Mouse Neural Progenitors.
I. Imayoshi, A. Isomura, Y. Harima, K. Kawaguchi, H. Kori, H. Miyachi, T. Fujiwara, F. Ishidate, and R. Kageyama (2013)
Science 342, 1203-1208
   Abstract »    Full Text »    PDF »
HES1 Is a Master Regulator of Glucocorticoid Receptor-Dependent Gene Expression.
J. R. Revollo, R. H. Oakley, N. Z. Lu, M. Kadmiel, M. Gandhavadi, and J. A. Cidlowski (2013)
Science Signaling 6, ra103
   Abstract »    Full Text »    PDF »
Transcript processing and export kinetics are rate-limiting steps in expressing vertebrate segmentation clock genes.
N. P. Hoyle and D. Ish-Horowicz (2013)
PNAS 110, E4316-E4324
   Abstract »    Full Text »    PDF »
The dynamics of genetic control in the cell: the good and bad of being late.
G. Tiana and M. H. Jensen (2013)
Phil Trans R Soc A 371, 20120469
   Abstract »    Full Text »    PDF »
Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model.
N. Bonzanni, A. Garg, K. A. Feenstra, J. Schutte, S. Kinston, D. Miranda-Saavedra, J. Heringa, I. Xenarios, and B. Gottgens (2013)
Bioinformatics 29, i80-i88
   Abstract »    Full Text »    PDF »
Spatial stochastic modelling of the Hes1 gene regulatory network: intrinsic noise can explain heterogeneity in embryonic stem cell differentiation.
M. Sturrock, A. Hellander, A. Matzavinos, and M. A. J. Chaplain (2013)
J R Soc Interface 10, 20120988
   Abstract »    Full Text »    PDF »
Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling.
J. Guiu, R. Shimizu, T. D'Altri, S. T. Fraser, J. Hatakeyama, E. H. Bresnick, R. Kageyama, E. Dzierzak, M. Yamamoto, L. Espinosa, et al. (2013)
J. Exp. Med. 210, 71-84
   Abstract »    Full Text »    PDF »
Noncanonical Notch Signaling Modulates Cytokine Responses of Dendritic Cells to Inflammatory Stimuli.
M. E. Gentle, A. Rose, L. Bugeon, and M. J. Dallman (2012)
J. Immunol. 189, 1274-1284
   Abstract »    Full Text »    PDF »
Variation in Candida albicans EFG1 Expression Enables Host-Dependent Changes in Colonizing Fungal Populations.
J. V. Pierce and C. A. Kumamoto (2012)
mBio 3, e00117-12
   Abstract »    Full Text »    PDF »
M. Maroto, R. A. Bone, and J. K. Dale (2012)
Development 139, 2453-2456
   Abstract »    Full Text »    PDF »
A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation.
H. P. Shih, J. L. Kopp, M. Sandhu, C. L. Dubois, P. A. Seymour, A. Grapin-Botton, and M. Sander (2012)
Development 139, 2488-2499
   Abstract »    Full Text »    PDF »
The Her7 node modulates the network topology of the zebrafish segmentation clock via sequestration of the Hes6 hub.
A. Trofka, J. Schwendinger-Schreck, T. Brend, W. Pontius, T. Emonet, and S. A. Holley (2012)
Development 139, 940-947
   Abstract »    Full Text »    PDF »
Novel cis-Regulatory Modules Control Expression of the Hairy and Enhancer of Split-1 (HES1) Transcription Factor in Myoblasts.
D. M. Jeziorska, G. Koentges, and K. W. Vance (2012)
J. Biol. Chem. 287, 5687-5697
   Abstract »    Full Text »    PDF »
Patterning embryos with oscillations: structure, function and dynamics of the vertebrate segmentation clock.
A. C. Oates, L. G. Morelli, and S. Ares (2012)
Development 139, 625-639
   Abstract »    Full Text »    PDF »
JAK/Stat signaling regulates heart precursor diversification in Drosophila.
A. N. Johnson, M. H. Mokalled, T. N. Haden, and E. N. Olson (2011)
Development 138, 4627-4638
   Abstract »    Full Text »    PDF »
Intronic delay is essential for oscillatory expression in the segmentation clock.
Y. Takashima, T. Ohtsuka, A. Gonzalez, H. Miyachi, and R. Kageyama (2011)
PNAS 108, 3300-3305
   Abstract »    Full Text »    PDF »
The Notch Target Hes1 Directly Modulates Gli1 Expression and Hedgehog Signaling: A Potential Mechanism of Therapeutic Resistance.
K. C. Schreck, P. Taylor, L. Marchionni, V. Gopalakrishnan, E. E. Bar, N. Gaiano, and C. G. Eberhart (2010)
Clin. Cancer Res. 16, 6060-6070
   Abstract »    Full Text »    PDF »
Coordinated sequential action of EGFR and Notch signaling pathways regulates proneural wave progression in the Drosophila optic lobe.
T. Yasugi, A. Sugie, D. Umetsu, and T. Tabata (2010)
Development 137, 3193-3203
   Abstract »    Full Text »    PDF »
Hes1, a new target for interleukin 1{beta} in chondrocytes.
S. Ottaviani, K. Tahiri, A. Frazier, Z. N. Hassaine, M.-F. Dumontier, W. Baschong, F. Rannou, M.-T. Corvol, J.-F. Savouret, and P. Richette (2010)
Ann Rheum Dis 69, 1488-1494
   Abstract »    Full Text »    PDF »
Random cell movement promotes synchronization of the segmentation clock.
K. Uriu, Y. Morishita, and Y. Iwasa (2010)
PNAS 107, 4979-4984
   Abstract »    Full Text »    PDF »
Dependence of the period on the rate of protein degradation in minimal models for circadian oscillations.
C. Gerard, D. Gonze, and A. Goldbeter (2009)
Phil Trans R Soc A 367, 4665-4683
   Abstract »    Full Text »    PDF »
Non-genetic heterogeneity of cells in development: more than just noise.
S. Huang (2009)
Development 136, 3853-3862
   Abstract »    Full Text »    PDF »
The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells.
T. Kobayashi, H. Mizuno, I. Imayoshi, C. Furusawa, K. Shirahige, and R. Kageyama (2009)
Genes & Dev. 23, 1870-1875
   Abstract »    Full Text »    PDF »
Structural Basis for Self-Renewal of Neural Progenitors in Cortical Neurogenesis.
G. Shioi, D. Konno, A. Shitamukai, and F. Matsuzaki (2009)
Cereb Cortex 19, i55-i61
   Abstract »    Full Text »    PDF »
Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity.
D. S. Wall, A. J. Mears, B. McNeill, C. Mazerolle, S. Thurig, Y. Wang, R. Kageyama, and V. A. Wallace (2009)
J. Cell Biol. 184, 101-112
   Abstract »    Full Text »    PDF »
Id2 Is Required for Specification of Dopaminergic Neurons during Adult Olfactory Neurogenesis.
M. C. Havrda, B. T. Harris, A. Mantani, N. M. Ward, B. R. Paolella, V. C. Cuzon, H. H. Yeh, and M. A. Israel (2008)
J. Neurosci. 28, 14074-14087
   Abstract »    Full Text »    PDF »
Bursting into the Nucleus.
G. R. Crabtree and I. A. Graef (2008)
Science Signaling 1, pe54
   Abstract »    Full Text »    PDF »
Dynamic Effect of Bortezomib on Nuclear Factor-{kappa}B Activity and Gene Expression in Tumor Cells.
M.-H. Sung, L. Bagain, Z. Chen, T. Karpova, X. Yang, C. Silvin, T. C. Voss, J. G. McNally, C. Van Waes, and G. L. Hager (2008)
Mol. Pharmacol. 74, 1215-1222
   Abstract »    Full Text »    PDF »
A C. elegans genome-scale microRNA network contains composite feedback motifs with high flux capacity.
N. J. Martinez, M. C. Ow, M. I. Barrasa, M. Hammell, R. Sequerra, L. Doucette-Stamm, F. P. Roth, V. R. Ambros, and A. J.M. Walhout (2008)
Genes & Dev. 22, 2535-2549
   Abstract »    Full Text »    PDF »
Coherent coupling of feedback loops: a design principle of cell signaling networks.
Y.-K. Kwon and K.-H. Cho (2008)
Bioinformatics 24, 1926-1932
   Abstract »    Full Text »    PDF »
HES-1 Is Involved in Adaptation of Adult Human {beta}-Cells to Proliferation In Vitro.
Y. Bar, H. A. Russ, S. Knoller, L. Ouziel-Yahalom, and S. Efrat (2008)
Diabetes 57, 2413-2420
   Abstract »    Full Text »    PDF »
Classic limb patterning models and the work of Dennis Summerbell.
J. L. Galloway and C. J. Tabin (2008)
Development 135, 2683-2687
   Abstract »    Full Text »    PDF »
Rate constants rather than biochemical mechanism determine behaviour of genetic clocks.
E. Conrad, A. E Mayo, A. J Ninfa, and D. B Forger (2008)
J R Soc Interface 5, S9-S15
   Abstract »    Full Text »    PDF »
cAMP-Dependent Signaling as a Core Component of the Mammalian Circadian Pacemaker.
J. S. O'Neill, E. S. Maywood, J. E. Chesham, J. S. Takahashi, and M. H. Hastings (2008)
Science 320, 949-953
   Abstract »    Full Text »    PDF »
Bayesian inference for dynamic transcriptional regulation; the Hes1 system as a case study.
E. A. Heron, B. Finkenstadt, and D. A. Rand (2007)
Bioinformatics 23, 2596-2603
   Abstract »    Full Text »    PDF »
Watch-ing out for chick limb development.
S. Pascoal and I. Palmeirim (2007)
Integr. Comp. Biol. 47, 382-389
   Abstract »    Full Text »    PDF »
Antiparallel Segregation of Notch Components in the Immunological Synapse Directs Reciprocal Signaling in Allogeneic Th:DC Conjugates.
W. H. Luty, D. Rodeberg, J. Parness, and Y. M. Vyas (2007)
J. Immunol. 179, 819-829
   Abstract »    Full Text »    PDF »
Delta Notch and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors.
A. Fischer and M. Gessler (2007)
Nucleic Acids Res. 35, 4583-4596
   Abstract »    Full Text »    PDF »
Ultradian oscillations of Stat, Smad, and Hes1 expression in response to serum.
S. Yoshiura, T. Ohtsuka, Y. Takenaka, H. Nagahara, K. Yoshikawa, and R. Kageyama (2007)
PNAS 104, 11292-11297
   Abstract »    Full Text »    PDF »
Oscillation patterns in negative feedback loops.
S. Pigolotti, S. Krishna, and M. H. Jensen (2007)
PNAS 104, 6533-6537
   Abstract »    Full Text »    PDF »
The Hes gene family: repressors and oscillators that orchestrate embryogenesis.
R. Kageyama, T. Ohtsuka, and T. Kobayashi (2007)
Development 134, 1243-1251
   Abstract »    Full Text »    PDF »
Regulation of dendritic-cell differentiation by bone marrow stroma via different Notch ligands.
P. Cheng, Y. Nefedova, C. A. Corzo, and D. I. Gabrilovich (2007)
Blood 109, 507-515
   Abstract »    Full Text »    PDF »
Ultradian Oscillators in Somite Segmentation and Other Biological Events.
R. Kageyama, S. Yoshiura, Y. Masamizu, and Y. Niwa (2007)
Cold Spring Harb Symp Quant Biol 72, 451-457
   Abstract »    PDF »
Estrogen-triggered delays in mammary gland gene expression during the estrous cycle: evidence for a novel timing system.
G. B Silberstein, K. Van Horn, E. Hrabeta-Robinson, and J. Compton (2006)
J. Endocrinol. 190, 225-239
   Abstract »    Full Text »    PDF »
Persistent and high levels of Hes1 expression regulate boundary formation in the developing central nervous system.
J. H. Baek, J. Hatakeyama, S. Sakamoto, T. Ohtsuka, and R. Kageyama (2006)
Development 133, 2467-2476
   Abstract »    Full Text »    PDF »
VEGF activates divergent intracellular signaling components to regulate retinal progenitor cell proliferation and neuronal differentiation.
T. Hashimoto, X.-M. Zhang, B. Y.-k. Chen, and X.-J. Yang (2006)
Development 133, 2201-2210
   Abstract »    Full Text »    PDF »
Modelling transcriptional feedback loops: the role of Gro/TLE1 in Hes1 oscillations.
S. Bernard, B. Cajavec, L. Pujo-Menjouet, M. C Mackey, and H. Herzel (2006)
Phil Trans R Soc A 364, 1155-1170
   Abstract »    Full Text »    PDF »
Real-time imaging of the somite segmentation clock: Revelation of unstable oscillators in the individual presomitic mesoderm cells.
Y. Masamizu, T. Ohtsuka, Y. Takashima, H. Nagahara, Y. Takenaka, K. Yoshikawa, H. Okamura, and R. Kageyama (2006)
PNAS 103, 1313-1318
   Abstract »    Full Text »    PDF »
Topology of biological networks and reliability of information processing.
K. Klemm and S. Bornholdt (2005)
PNAS 102, 18414-18419
   Abstract »    Full Text »    PDF »
Zebrafish bandoneon mutants display behavioral defects due to a mutation in the glycine receptor {beta}-subunit.
H. Hirata, L. Saint-Amant, G. B. Downes, W. W. Cui, W. Zhou, M. Granato, and J. Y. Kuwada (2005)
PNAS 102, 8345-8350
   Abstract »    Full Text »    PDF »
Impairment of Thymocyte Development by Dominant-Negative Kuzbanian (ADAM-10) Is Rescued by the Notch Ligand, Delta-1.
J. O. Manilay, A. C. Anderson, C. Kang, and E. A. Robey (2005)
J. Immunol. 174, 6732-6741
   Abstract »    Full Text »    PDF »
The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta.
E. C. Lai, F. Roegiers, X. Qin, Y. N. Jan, and G. M. Rubin (2005)
Development 132, 2319-2332
   Abstract »    Full Text »    PDF »
Protein Kinase C Activates Human Lipocalin-type Prostaglandin D Synthase Gene Expression through De-repression of Notch-HES Signaling and Enhancement of AP-2{beta} Function in Brain-derived TE671 Cells.
K. Fujimori, K. Kadoyama, and Y. Urade (2005)
J. Biol. Chem. 280, 18452-18461
   Abstract »    Full Text »    PDF »
The Strength of Indecisiveness: Oscillatory Behavior for Better Cell Fate Determination.
G. Lahav (2004)
Sci. STKE 2004, pe55
   Abstract »    Full Text »    PDF »
Clock Genes in Cell Clocks: Roles, Actions, and Mysteries.
H. Okamura (2004)
J Biol Rhythms 19, 388-399
   Abstract »    PDF »
Segmentation in vertebrates: clock and gradient finally joined.
A. Aulehla and B. G. Herrmann (2004)
Genes & Dev. 18, 2060-2067
   Abstract »    Full Text »    PDF »
Ribosomal protein L24 defect in Belly spot and tail (Bst), a mouse Minute.
E. R. Oliver, T. L. Saunders, S. A. Tarle, and T. Glaser (2004)
Development 131, 3907-3920
   Abstract »    Full Text »    PDF »
receptor tyrosine phosphatase {psi} is required for Delta/Notch signalling and cyclic gene expression in the presomitic mesoderm.
B. Aerne and D. Ish-Horowicz (2004)
Development 131, 3391-3399
   Abstract »    Full Text »    PDF »
Helt, a Novel Basic-Helix-Loop-Helix Transcriptional Repressor Expressed in the Developing Central Nervous System.
T. Nakatani, E. Mizuhara, Y. Minaki, Y. Sakamoto, and Y. Ono (2004)
J. Biol. Chem. 279, 16356-16367
   Abstract »    Full Text »    PDF »
Two zebrafish Notch-dependent hairy/Enhancer-of-split-related genes, her6 and her4, are required to maintain the coordination of cyclic gene expression in the presomitic mesoderm.
A. Pasini, Y.-J. Jiang, and D. G. Wilkinson (2004)
Development 131, 1529-1541
   Abstract »    Full Text »    PDF »
Identification of p53 regulators by genome-wide functional analysis.
Q. Huang, A. Raya, P. DeJesus, S.-H. Chao, K. C. Quon, J. S. Caldwell, S. K. Chanda, J. C. Izpisua-Belmonte, and P. G. Schultz (2004)
PNAS 101, 3456-3461
   Abstract »    Full Text »    PDF »
HES-1, a Novel Target Gene for the Aryl Hydrocarbon Receptor.
J. S. Thomsen, S. Kietz, A. Strom, and J.-A. Gustafsson (2004)
Mol. Pharmacol. 65, 165-171
   Abstract »    Full Text »    PDF »
Notch signaling in the immune system.
G. F. Hoyne (2003)
J. Leukoc. Biol. 74, 971-981
   Abstract »    Full Text »
The Segmentation Clock: Converting Embryonic Time into Spatial Pattern.
O. Pourquie (2003)
Science 301, 328-330
   Abstract »    Full Text »    PDF »
Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock.
Y. Bessho, H. Hirata, Y. Masamizu, and R. Kageyama (2003)
Genes & Dev. 17, 1451-1456
   Abstract »    Full Text »    PDF »
Oscillatory nucleocytoplasmic shuttling of the general stress response transcriptional activators Msn2 and Msn4 in Saccharomyces cerevisiae.
M. Jacquet, G. Renault, S. Lallet, J. De Mey, and A. Goldbeter (2003)
J. Cell Biol. 161, 497-505
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882