Mitotic trigger waves are waves of Cyclin-dependent kinase 1 (Cdk1) activity in cells that originate from pacemaker regions of the nucleus and propagate through the cytoplasm.Nolet, F. E., Vandervelde, A., Vanderbeke, A., Piñeros, L., Chang, J. B., & Gelens, L. (2020). Nuclei determine the spatial origin of mitotic waves. ELife, 9. Because trigger waves do not decrease in speed or amplitude during their propagation, they are more reliable at conveying molecular information across greater distances compared to simple diffusion.Gelens, L., Anderson, G. A., & Ferrell, J. E. (2014). Spatial trigger waves: positive feedback gets you a long way. Molecular Biology of the Cell, 25(22), 3486–3493. Therefore, trigger waves ensure that different spatial components of cells can proceed through processes of mitosis in a rapid, timely manner.Chang, J. B., & Ferrell Jr, J. E. (2013). Mitotic trigger waves and the spatial coordination of the Xenopus cell cycle. Nature, 500(7464), 603–607. This wave model is considered particularly relevant to the development of large eggs such as that of the African clawed frog (Xenopus laevis), where simple diffusion cannot carry information quickly enough to synchronize the entire cell during mitosis.Nolet, F. E., Vandervelde, A., Vanderbeke, A., Piñeros, L., Chang, J. B., & Gelens, L. (2020). Nuclei determine the spatial origin of mitotic waves. ELife, 9.

Biochemical basis

Using X. laevis egg extract as a model, it has been discovered that a cell’s entry into mitosis is regulated by the activation of the cyclin B/Cdk1 complex.Solomon, M. J., Glotzer, M., Lee, T. H., Philippe, M., & Kirschner, M. W. (1990). Cyclin activation of p34cdc2. Cell, 63(5), 1013–1024. https://doi.org/10.1016/0092-8674(90)90504-8 ‌ The relationship between cyclin B/Cdk1 activation and cyclin concentration exhibits hysteresis, as a result of interactions between the cyclin B/Cdk1-Cdc25 positive feedback loop, the cyclin B/Cdk1-Wee1 inhibition positive feedback loop and the Cdk1-Fizzy negative feedback loop.Sha, W., Moore, J., Chen, K., Lassaletta, A. D., Yi, C.-S., Tyson, J. J., & Sible, J. C. (2003). Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts. Proceedings of the National Academy of Sciences, 100(3), 975–980.‌ The bistability of the cyclin B/Cdk1 regulation system potentially gives rise to trigger wave propagation.Novak, B., & Tyson, J. J. (1993). Modeling the Cell Division Cycle: M-phase Trigger, Oscillations, and Size Control. Journal of Theoretical Biology, 165(1), 101–134.Tyson, J. J., & Keener, J. P. (1988). Singular perturbation theory of traveling waves in excitable media (a review). 32(3), 327–361. https://doi.org/10.1016/0167-2789(88)90062-0 The waves are coordinated by pacemaker regions whose molecular waves oscillate more rapidly than the rest of the cell. The pacemakers are hypothesized to be located at the nuclei or centrosomes, with current evidence suggesting that the nuclei are more likely to be the origin of mitotic trigger wavesNolet, F. E., Vandervelde, A., Vanderbeke, A., Piñeros, L., Chang, J. B., & Gelens, L. (2020). Nuclei determine the spatial origin of mitotic waves. ELife, 9.Chang, J. B., & Ferrell Jr, J. E. (2013). Mitotic trigger waves and the spatial coordination of the Xenopus cell cycle. Nature, 500(7464), 603–607.

Mathematical model

The speed of mitotic trigger waves can be estimated by Luther’s equation, v ≈ 2(D/τ)1/2, where D is the diffusion coefficient and τ is related to the time for the bistable system to reach either its on- or off- switch threshold.Chang, J. B., & Ferrell Jr, J. E. (2013). Mitotic trigger waves and the spatial coordination of the Xenopus cell cycle. Nature, 500(7464), 603–607.Luther, R. Raumliche fortplanzung chimischer reaktionen. Z. Elektrochemie 12,596–600 (1906). Using this model to predict the propagation of trigger waves, the signal takes 2–5 minutes to travel from the pronuclei to the animal pole.Chang, J. B., & Ferrell Jr, J. E. (2013). Mitotic trigger waves and the spatial coordination of the Xenopus cell cycle. Nature, 500(7464), 603–607.

Mitotic trigger waves are most rapidly propagated at a 1x cytoplasmic concentration, but can be generated and propagated across a wide range of cellular environments.Huang, J.-H., Chen, Y., William, Saman Tabatabaee, & Ferrell, J. E. (2024). Robust trigger wave speed in Xenopus cytoplasmic extracts. Nature Communications, 15(1). The propagation speed of the waves are robust when encountering fluctuations of the cellular environment, because an increase in reactant concentration is countered by a decrease in viscosity.Huang, J.-H., Chen, Y., William, Saman Tabatabaee, & Ferrell, J. E. (2024). Robust trigger wave speed in Xenopus cytoplasmic extracts. Nature Communications, 15(1).

Role in cell cycle progression

Trigger waves are an alternative to the random walk diffusion model of intracellular information transfer, and is significantly more efficient at a millimeter-to-meter distance range.Chang, J. B., & Ferrell Jr, J. E. (2013). Mitotic trigger waves and the spatial coordination of the Xenopus cell cycle. Nature, 500(7464), 603–607. Before the role of trigger waves in coordinating mitosis is discovered, the paradigm has been identified in neuronal action potentialBakkum, D. J., Frey, U., Radivojevic, M., Russell, T. L., Müller, J., Fiscella, M., Takahashi, H., & Hierlemann, A. (2013). Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites. Nature Communications, 4(1).‌ and cyclic AMP waves.Tyson, J. J. & Keener, J. P. Singular perturbation theory of traveling waves in excitable media (a review). Physica D 32, 327–361 (1988). In mitosis, trigger waves are essential to embryonic development for organisms including X.laevis and fruit flies (D. melanogaster).Wilmott, Z. M., & Raff, J. W. (2022). Cell cycle: Making waves to coordinate the entry into mitosis. Current Biology, 32(22), R1262–R1264.

With the previously accepted model of random walk diffusion, Cdk1 activation would coordinate synchronous entry into mitosis for somatic cells with a ~10μm diameter, but the process would take exponentially longer for embryonic cells with a diameter of ~600μm, making the model highly impractical.Chang, J. B., & Ferrell Jr, J. E. (2013). Mitotic trigger waves and the spatial coordination of the Xenopus cell cycle. Nature, 500(7464), 603–607. With the mitotic trigger wave model, the propagation of the mitotic signal reaches distant parts of the cell within minutes, which is a more accurate representation of actual mitotic signal propagation rates.Goldberger, R. F., & Yamamoto, K. R. (2013). Biological Regulation and Development. Springer Science & Business Media.

Role in embryonic development

Mitotic trigger waves can potentially explain the mitotic coordination during early embryonic development. Early-stage embryos of metazoans undergo rounds of near-synchronous cell division, and the mechanism with which cells across a ~1mm embryo can maintain synchronized division is still unclear.O'Farrell, P. H., Stumpff, J., & Su, T. T. (2004). Embryonic cleavage cycles: how is a mouse like a fly?. Current Biology, 14(1), R35–R45. While the mitotic coordination in wild type Drosophila exhibits a "sweep" wave, an alternative reaction-diffusion model with a dependency on the S-phase Cdk1 activation rate, the mitotic signal wave reverts back to a classic trigger wave when Cyclin A and Cyclin B are mutated in the flies to slow the entry into mitosis.Massimo Vergassola, Deneke, V. E., & Stefano Di Talia. (2018). Mitotic waves in the early embryogenesis of Drosophila : Bistability traded for speed. Proceedings of the National Academy of Sciences of the United States of America, 115(10).

References

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