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Mechanism of shape determination in motile cells

Nature volume 453, pages 475–480 (2008)Cite this article

Abstract

The shape of motile cells is determined by many dynamic processes spanning several orders of magnitude in space and time, from local polymerization of actin monomers at subsecond timescales to global, cell-scale geometry that may persist for hours. Understanding the mechanism of shape determination in cells has proved to be extremely challenging due to the numerous components involved and the complexity of their interactions. Here we harness the natural phenotypic variability in a large population of motile epithelial keratocytes from fish (Hypsophrys nicaraguensis) to reveal mechanisms of shape determination. We find that the cells inhabit a low-dimensional, highly correlated spectrum of possible functional states. We further show that a model of actin network treadmilling in an inextensible membrane bag can quantitatively recapitulate this spectrum and predict both cell shape and speed. Our model provides a simple biochemical and biophysical basis for the observed morphology and behaviour of motile cells.

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Figure 1: Keratocyte shapes are described by four primary shape modes.
Figure 2: Quantitative and correlative analysis of keratocyte morphology and speed.
Figure 3: A quantitative model explains the main features of keratocyte shapes.
Figure 4: An extended model predicts lamellipodial curvature and the relationship between speed and morphology.

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Acknowledgements

We thank C. Lacayo, C. Wilson and M. Kozlov for discussion, and P. Yam, C. Lacayo, E. Braun and T. Pollard for comments on the manuscript. K.K. is a Damon Runyon Postdoctoral Fellow supported by the Damon Runyon Cancer Research Foundation, and a Horev Fellow supported by the Taub Foundations. A.M. is supported by the National Science Foundation grant number DMS-0315782 and the National Institutes of Health Cell Migration Consortium grant number NIGMS U54 GM64346. J.A.T. is supported by grants from the National Institutes of Health and the American Heart Association.

Author Contributions Z.P., K.K., E.L.B., G.M.A. and J.A.T. designed the experiments. K.K., G.M.A., E.L.B. and Z.P. performed the experiments. Z.P. together with K.K., A.M., G.M.A. and E.L.B. analysed the data. A.M. together with K.K., Z.P., E.L.B., G.M.A. and J.A.T. developed the model. G.M. provided the kabiramide C probe. Z.P., K.K., A.M. and J.A.T. wrote the paper. All authors discussed the results and commented on the manuscript.

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Author notes

  1. Kinneret Keren and Zachary Pincus: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, and,

    Kinneret Keren, Zachary Pincus, Greg M. Allen, Erin L. Barnhart & Julie A. Theriot

  2. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA,

    Julie A. Theriot

  3. Department of Physics, Technion- Israel Institute of Technology, Haifa 32000, Israel

    Kinneret Keren

  4. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520, USA,

    Zachary Pincus

  5. Department of Physiology, University of Wisconsin at Madison, Madison, Wisconsin 53706, USA,

    Gerard Marriott

  6. Department of Neurobiology, Physiology and Behavior and Department of Mathematics, University of California, Davis, California 95616, USA,

    Alex Mogilner

Authors
  1. Kinneret Keren
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  2. Zachary Pincus
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Corresponding author

Correspondence to Julie A. Theriot.

Supplementary information

Supplementary information

This file contains Supplementary Discussion, Supplementary Methods and Supplementary Figures S1-S8 with Legends. The file includes: a table of model assumptions and their rationales; mathematical derivations of the model and equations presented in the main text; further discussion of the relation of the model to experimental data and other model predictions; discussion of the limitations of the model; analysis of the results of the molecular perturbations; a rationale for ruling out alternate models; and supplementary methods including shape-alignment algorithms. (PDF 4973 kb)

Supplementary information

The file contains Supplementary Data with multiple files containing the measurements presented in the main and supplementary text, including: live cell populations (stained with kabiramide C and unstained) imaged at 30 seconds apart; several live cells followed through time; a fixed-cell population; populations of live cells perturbed with various pharmacological agents; and time-lapse measurements of cells challenged with DMSO. (zip-compressed comma-separated value files.(zip-compressed comma-separated value files. (ZIP 169 kb)

Supplementary information

The file contains Supplementary Movie 1. This movie shows a motile keratocyte before, during and after transient treatment with DMSO. The time lapse covers a period of about 28 min (the DMSO perturbation is applied about 6 min into the movie), and the field of view is 87 ?m wide. The movie clearly illustrates how the cell recovers from an acute perturbation and resumes its original shape and speed. (MOV 242 kb)

Supplementary information

The file contains Supplementary Movie 2. This movie shows phase-contrast (left) and fluorescence (right) images of a kabiramide C stained "coherent" keratocyte. The time lapse covers a period of about 6 min, and the field of view is 56 ?m wide. (MOV 1935 kb)

Supplementary information

The file contains Supplementary Movie 3. This movie shows phase-contrast (left) and fluorescence (right) images of a kabiramide C stained "decoherent" keratocyte. The time lapse covers a period of about 11 min, and the field of view is 56 ?m wide. (MOV 2977 kb)

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Keren, K., Pincus, Z., Allen, G. et al. Mechanism of shape determination in motile cells. Nature 453, 475–480 (2008). https://doi.org/10.1038/nature06952

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