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Noise-resistant and synchronized oscillation of the segmentation clock


Periodic somite segmentation in vertebrate embryos is controlled by the ‘segmentation clock’, which consists of numerous cellular oscillators. Although the properties of a single oscillator, driven by a hairy negative-feedback loop, have been investigated, the system-level properties of the segmentation clock remain largely unknown. To explore these characteristics, we have examined the response of a normally oscillating clock in zebrafish to experimental stimuli using in vivo mosaic experiments and mathematical simulation. We demonstrate that the segmentation clock behaves as a coupled oscillator, by showing that Notch-dependent intercellular communication, the activity of which is regulated by the internal hairy oscillator, couples neighbouring cells to facilitate synchronized oscillation. Furthermore, the oscillation phase of individual oscillators fluctuates due to developmental noise such as stochastic gene expression and active cell proliferation. The intercellular coupling was found to have a crucial role in minimizing the effects of this noise to maintain coherent oscillation.

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Figure 1: Synchronized oscillation of her1 and deltaC in the posterior PSM.
Figure 2: Effects of actively signalling cells upon synchronized oscillation.
Figure 3: Fluctuated oscillation of her1.
Figure 4: Coupling-assisted phase synchronization.


  1. Winfree, A. T. Biological rhythms and the behavior of populations of coupled oscillators. J. Theor. Biol. 16, 15–42 (1967)

    CAS  Article  Google Scholar 

  2. Winfree, A. T. The Geometry of Biological Time (Springer, New York, 2000)

    MATH  Google Scholar 

  3. Palmeirim, I., Henrique, D., Ish-Horowicz, D. & Pourquié, O. Avian hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis. Cell 91, 639–648 (1997)

    CAS  Article  Google Scholar 

  4. Pourquié, O. The segmentation clock: converting embryonic time into spatial pattern. Science 301, 328–330 (2003)

    ADS  Article  Google Scholar 

  5. Saga, Y. & Takeda, H. The making of the somite: molecular events in vertebrate segmentation. Nature Rev. Genet. 2, 835–845 (2001)

    CAS  Article  Google Scholar 

  6. Dale, J. K. et al. Periodic notch inhibition by lunatic fringe underlies the chick segmentation clock. Nature 421, 275–278 (2003)

    ADS  CAS  Article  Google Scholar 

  7. Cooke, J. Control of somite number during morphogenesis of a vertebrate, Xenopus laevis. Nature 254, 196–199 (1975)

    ADS  CAS  Article  Google Scholar 

  8. Cooke, J. & Zeeman, E. C. A clock and wavefront model for control of the number of repeated structures during animal morphogenesis. J. Theor. Biol. 58, 455–476 (1976)

    CAS  Article  Google Scholar 

  9. Cooke, J. A gene that resuscitates a theory—somitogenesis and a molecular oscillator. Trends Genet. 14, 85–88 (1998)

    CAS  Article  Google Scholar 

  10. Holley, S. A., Julich, D., Rauch, G. J., Geisler, R. & Nusslein-Volhard, C. her1 and the notch pathway function within the oscillator mechanism that regulates zebrafish somitogenesis. Development 129, 1175–1183 (2002)

    CAS  PubMed  Google Scholar 

  11. Hirata, H. et al. Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science 298, 840–843 (2002)

    ADS  CAS  Article  Google Scholar 

  12. Bessho, Y., Hirata, H., Masamizu, Y. & Kageyama, R. Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock. Genes Dev. 17, 1451–1456 (2003)

    CAS  Article  Google Scholar 

  13. Henry, C. A. et al. Two linked hairy/Enhancer of split-related zebrafish genes, her1 and her7, function together to refine alternating somite boundaries. Development 129, 3693–3704 (2002)

    CAS  PubMed  Google Scholar 

  14. Oates, A. C. & Ho, R. K. Hairy/E(spl)-related (Her) genes are central components of the segmentation oscillator and display redundancy with the Delta/Notch signaling pathway in the formation of anterior segmental boundaries in the zebrafish. Development 129, 2929–2946 (2002)

    CAS  PubMed  Google Scholar 

  15. Jiang, Y. J. et al. Notch signalling and the synchronization of the somite segmentation clock. Nature 408, 475–479 (2000)

    ADS  CAS  Article  Google Scholar 

  16. Lewis, J. Autoinhibition with transcriptional delay: a simple mechanism for the zebrafish somitogenesis oscillator. Curr. Biol. 13, 1398–1408 (2003)

    CAS  Article  Google Scholar 

  17. Holley, S. A., Geisler, R. & Nusslein-Volhard, C. Control of her1 expression during zebrafish somitogenesis by a delta-dependent oscillator and an independent wave-front activity. Genes Dev. 14, 1678–1690 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Sawada, A. et al. Fgf/MAPK signalling is a crucial positional cue in somite boundary formation. Development 128, 4873–4880 (2001)

    CAS  PubMed  Google Scholar 

  19. Dubrulle, J., McGrew, M. J. & Pourquié, O. FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell 106, 219–232 (2001)

    CAS  Article  Google Scholar 

  20. McAdams, H. H. & Arkin, A. Stochastic mechanisms in gene expression. Proc. Natl Acad. Sci. USA 94, 814–819 (1997)

    ADS  CAS  Article  Google Scholar 

  21. Shav-Tal, Y. et al. Dynamics of single mRNPs in nuclei of living cells. Science 304, 1797–1800 (2004)

    ADS  CAS  Article  Google Scholar 

  22. Blake, W. J., Kærn, M., Cantor, C. R. & Collins, J. J. Noise in eukaryotic gene expression. Nature 422, 633–637 (2003)

    ADS  CAS  Article  Google Scholar 

  23. Prescott, D. M. & Bender, M. A. Synthesis of RNA and protein during mitosis in mammalian tissue culture cells. Exp. Cell Res. 26, 260–268 (1962)

    Article  Google Scholar 

  24. Nagoshi, E. et al. Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells. Cell 119, 693–705 (2004)

    CAS  Article  Google Scholar 

  25. Welsh, D. K., Yoo, S. H., Liu, A. C., Takahashi, J. S. & Kay, S. A. Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr. Biol. 14, 2289–2295 (2004)

    CAS  Article  Google Scholar 

  26. Ueda, H. R., Hirose, K. & Iino, M. Intercellular coupling mechanism for synchronized and noise-resistant circadian oscillators. J. Theor. Biol. 216, 501–512 (2002)

    MathSciNet  CAS  Article  Google Scholar 

  27. Rida, P. C., Le Minh, N. & Jiang, Y. J. A Notch feeling of somite segmentation and beyond. Dev. Biol. 265, 2–22 (2004)

    CAS  Article  Google Scholar 

  28. Evrard, Y. A., Lun, Y., Aulehla, A., Gan, L. & Johnson, R. L. lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394, 377–381 (1998)

    ADS  CAS  Article  Google Scholar 

  29. Zhang, N. & Gridley, T. Defects in somite formation in lunatic fringe-deficient mice. Nature 394, 374–377 (1998)

    ADS  CAS  Article  Google Scholar 

  30. Aulehla, A. et al. Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Dev. Cell 4, 395–406 (2003)

    CAS  Article  Google Scholar 

  31. Ma'ayan, A. et al. Formation of regulatory patterns during signal propagation in a mammalian cellular network. Science 309, 1078–1083 (2005)

    ADS  CAS  Article  Google Scholar 

  32. Brandman, O., Ferrell, J. E. Jr, Li, R. & Meyer, T. Interlinked fast and slow positive feedback loops drive reliable cell decisions. Science 310, 496–498 (2005)

    ADS  MathSciNet  CAS  Article  Google Scholar 

  33. Bornholdt, S. Systems biology. Less is more in modeling large genetic networks. Science 310, 449–451 (2005)

    CAS  Article  Google Scholar 

  34. Waddington, C. Canalization of development and the inheritance of acquired characters. Nature 150, 563–565 (1942)

    ADS  Article  Google Scholar 

  35. Houchmandzadeh, B., Wieschaus, E. & Leibler, S. Establishment of developmental precision and proportions in the early Drosophila embryo. Nature 415, 798–802 (2002)

    ADS  CAS  Article  Google Scholar 

  36. Lucchetta, E. M., Lee, J. H., Fu, L. A., Patel, N. H. & Ismagilov, R. F. Dynamics of Drosophila embryonic patterning network perturbed in space and time using microfluidics. Nature 434, 1134–1138 (2005)

    ADS  CAS  Article  Google Scholar 

  37. Freeman, M. Feedback control of intercellular signalling in development. Nature 408, 313–319 (2000)

    ADS  CAS  Article  Google Scholar 

  38. Eldar, A. et al. Robustness of the BMP morphogen gradient in Drosophila embryonic patterning. Nature 419, 304–308 (2002)

    ADS  CAS  Article  Google Scholar 

  39. Hall, B. K. & Olson, W. M. Keywords and Concepts in Evolutionary Developmental Biology (Harvard Univ. Press, Cambridge, Massachusetts, 2003)

    Google Scholar 

  40. von Dassow, G., Meir, E., Munro, E. M. & Odell, G. M. The segment polarity network is a robust developmental module. Nature 406, 188–192 (2000)

    ADS  CAS  Article  Google Scholar 

  41. Ingolia, N. T. Topology and robustness in the Drosophila segment polarity network. PLoS Biol. 2, e123 (2004)

    Article  Google Scholar 

  42. Kosman, D. et al. Multiplex detection of RNA expression in Drosophila embryos. Science 305, 846 (2004)

    CAS  Article  Google Scholar 

  43. Julich, D. et al. beamter/deltaC and the role of Notch ligands in the zebrafish somite segmentation, hindbrain neurogenesis and hypochord differentiation. Dev. Biol. 286, 391–404 (2005)

    Article  Google Scholar 

  44. Hirata, H. et al. Instability of Hes7 protein is crucial for the somite segmentation clock. Nature Genet. 36, 750–754 (2004)

    CAS  Article  Google Scholar 

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We thank T. Fujimori for providing human histone 2B–EGFP cDNA; D. Tautz for the technical advice regarding the synthesis of intronic probes for her1; T. Tomita and T. Iwatsubo for their gift of DAPT; and Y. J. Jiang for Notch1a mutant (desth35b). We also thank H. Ueda, T. Uemura, M. Takeichi, A. Takamatsu and J. Lewis for their advice and for critical reading of the manuscript. This work was supported by a postdoctoral fellowship and in part by Grants-in-Aid for Scientific Research Priority Area Genome Science and Organized Research Combination System, both of which are from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Correspondence to Kazuki Horikawa or Hiroyuki Takeda.

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Supplementary information

Supplementary Notes 1

Description of her1 and deltaC oscillation with Supplementary Figure 1–2. (DOC 1013 kb)

Supplementary Notes 2

Description of clock & wavefront model and segment-shift phenotype with Supplementary Figure 3–5. (DOC 458 kb)

Supplementary Notes 3

Description of mathematical simulations with Supplementary Figure 6–9. (DOC 627 kb)

Supplementary Figure 10

Randomized sub-cellular localization of her1 transcripts (green) in the posterior PSM of DAPT-treated embryo. Nuclear- or cytoplasmic-her1 transcripts are indicated by arrowheads and arrows, respectively. Magenta indicates nuclei. Bar, 20mm. (JPG 145 kb)

Supplementary Movie 1

This movie is a source of Supplementary Figure 6 showing the simulated effect of the actively signalling cell on the synchronized oscillation. (MOV 178 kb)

Supplementary Movie 2

This movie is a source of Figure 3a–b showing dorsal view of a normal PSM expressing Histone2B–GFP. Pseudo-colour labelled nuclei indicate cells which have experienced mitosis in right side of the posterior PSM during one cycle of oscillation (from 8-somite to 9-somite stage). Images were acquired at every minute for 30 minutes. (MOV 5123 kb)

Supplementary Movie 3

This movie is a source of Figure 8 showing the phase synchronization in linearly aligned 15 cells. One of transplanted cells (delayed by 1/4-cycle) is indicated by magenta. (MOV 264 kb)

Supplementary Movie 4

Schematic representation of the clock & wavefront model. Clock oscillation in the entire PSM and regressing wavefront are indicated by green and magenta, respectively. Oscillation phase of the clock is fixed at the time of interaction with the wavefront, eventually leaving segmental pattern of the somite. Anterior to the top. (MOV 679 kb)

Supplementary Movie 5

Segment-shift phenotype caused by the accelerated oscillation of the segmentation clock. The segmentation clock with higher frequency (blue) encounters the wavefront more anterior region, leaving smaller segments compared to normal condition. (MOV 133 kb)

Supplementary Table 1

Mitotic activity in the posterior PSM of normal, DMSO or DAPT-treated embryos at 8- to 9-somite stage. (DOC 30 kb)

Supplementary Methods

This file contains additional details on the methods used in this study. (DOC 26 kb)

Supplementary References

References in Supplementary Notes 1–3 and Supplementary Methods. (DOC 27 kb)

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Horikawa, K., Ishimatsu, K., Yoshimoto, E. et al. Noise-resistant and synchronized oscillation of the segmentation clock. Nature 441, 719–723 (2006).

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