Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Dynamics extracted from fixed cells reveal feedback linking cell growth to cell cycle

Nature volume 494, pages 480–483 (2013)Cite this article

Subjects

Abstract

Biologists have long been concerned about what constrains variation in cell size, but progress in this field has been slow and stymied by experimental limitations1. Here we describe a new method, ergodic rate analysis (ERA), that uses single-cell measurements of fixed steady-state populations to accurately infer the rates of molecular events, including rates of cell growth. ERA exploits the fact that the number of cells in a particular state is related to the average transit time through that state2. With this method, it is possible to calculate full time trajectories of any feature that can be labelled in fixed cells, for example levels of phosphoproteins or total cellular mass. Using ERA we find evidence for a size-discriminatory process at the G1/S transition that acts to decrease cell-to-cell size variation.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Dynamic information from static data using ERA.
Figure 2: Calculation of growth as a function of cell cycle progression using ERA.
Figure 3: Rate of cell growth as a function of size and cell cycle.
Figure 4: Effects of drug treatments on size variability at G1 exit.

Similar content being viewed by others

References

  1. Mitchison, J. M. Growth during the cell cycle. Int. Rev. Cytol. 226, 165–258 (2003)

    Article  CAS  Google Scholar 

  2. Deen, W. M. Analysis of Transport Phenomena 2nd edn (Oxford University Press, 2012)

    Google Scholar 

  3. Sakaue-Sawano, A. et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell 132, 487–498 (2008)

    Article  CAS  Google Scholar 

  4. Mitchison, J. M. The Biology of the Cell Cycle 128 (University Press, 1971)

    Google Scholar 

  5. Popescu, G. et al. Optical imaging of cell mass and growth dynamics. Am. J. Physiol. Cell Physiol. 295, C538–C544 (2008)

    Article  CAS  Google Scholar 

  6. Mir, M. et al. Optical measurement of cycle-dependent cell growth. Proc. Natl Acad. Sci. USA 108, 13124–13129 (2011)

    Article  ADS  CAS  Google Scholar 

  7. Son, S. et al. Direct observation of mammalian cell growth and size regulation. Nature Methods 9, 910–912 (2012)

    Article  CAS  Google Scholar 

  8. Killander, D. & Zetterberg, A. A quantitative cytochemical investigation of the relationship between cell mass and initiation of DNA synthesis in mouse fibroblasts in vitro. Exp. Cell Res. 40, 12–20 (1965)

    Article  CAS  Google Scholar 

  9. Hendrix, R. W. & Zwaan, J. Cell shape regulation and cell cycle in embryonic lens cells. Nature 247, 145–147 (1974)

    Article  ADS  CAS  Google Scholar 

  10. Tzur, A., Kafri, R., LeBleu, V. S., Lahav, G. & Kirschner, M. W. Cell growth and size homeostasis in proliferating animal cells. Science 325, 167–171 (2009)

    Article  ADS  CAS  Google Scholar 

  11. Jacobberger, J. W., Avva, J., Sreenath, S. N., Weis, M. C. & Stefan, T. Dynamic epitope expression from static cytometry data: principles and reproducibility. PLoS ONE 7, e30870 (2012)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Klein, Y. Merbl, S. Tal and J. Toettcher for consistent and valuable insights at the beginning of and throughout this project. We thank J. Waters and the staff of The Nikon Imaging Center at Harvard Medical School for help and support. We especially thank R. Ward for her critique of the paper and the National Institute of General Medical Sciences (GM26875) for support of this work.

Author information

Author notes

  1. Ran Kafri and Jason Levy: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Ran Kafri, Miriam B. Ginzberg, Seungeun Oh, Galit Lahav & Marc W. Kirschner

  2. Department of Mathematics and Statistics, University of Ottawa, Ottawa, K1N 6N5, Ontario, Canada

    Jason Levy

Authors
  1. Ran Kafri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jason Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miriam B. Ginzberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seungeun Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Galit Lahav
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marc W. Kirschner
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.K. and J.L. developed the method (ERA) for extracting dynamic information and calculating feedback spectra from fixed populations, designed algorithms, wrote all image-processing software and analysed data. R.K. designed all experiments and wrote the manuscript. J.L. contributed significantly to all conceptual challenges and to writing the manuscript. M.B.G. contributed conceptually on levels of the study, made many important measurements and calculations and contributed to the writing of the manuscript. S.O. provided interferometry-derived cell mass measurements. G.L. and M.W.K. contributed to the formulation of the problem, development of the ideas and the writing of the manuscript.

Corresponding author

Correspondence to Marc W. Kirschner.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data, which includes Supplementary Figures 1-22 and additional references (see Contents for more details). (PDF 5477 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kafri, R., Levy, J., Ginzberg, M. et al. Dynamics extracted from fixed cells reveal feedback linking cell growth to cell cycle. Nature 494, 480–483 (2013). https://doi.org/10.1038/nature11897

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11897

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing