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Noise-resistant and synchronized oscillation of the segmentation clock

Naturevolume 441pages719723 (2006) | Download Citation



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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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.

Author information

Author notes

  1. Kazuki Horikawa, Kana Ishimatsu and Eiichi Yoshimoto: *These authors contributed equally to this work


  1. Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Hongo 7-3-1, 113-0033, Japan

    • Kazuki Horikawa
    • , Kana Ishimatsu
    •  & Hiroyuki Takeda
  2. Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Nagoya, 464-8602, Japan

    • Eiichi Yoshimoto
    •  & Shigeru Kondo


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Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kazuki Horikawa or Hiroyuki Takeda.

Supplementary information

  1. Supplementary Notes 1

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

  2. Supplementary Notes 2

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

  3. Supplementary Notes 3

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

  4. 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)

  5. 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)

  6. 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)

  7. 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)

  8. 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)

  9. 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)

  10. 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)

  11. Supplementary Methods

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

  12. Supplementary References

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

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