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A hierarchy of protein patterns robustly decodes cell shape information

Abstract

Many cellular processes, such as cell division1,2,3, cell motility4, wound healing5 and tissue folding6,7, rely on the precise positioning of proteins on the membrane. Such protein patterns emerge from a combination of protein interactions, transport, conformational state changes and chemical reactions at the molecular level8. Recent experimental and theoretical work clearly demonstrates the role of geometry, including membrane curvature9,10,11 and local cytosolic-to-membrane ratios12,13, and advective cortical flow in modulating membrane protein patterns. However, it remains unclear how these proteins achieve robust spatiotemporal organization on the membrane during the dynamic cell shape changes involved in physiological processes. Here we use oocytes of the starfish Patiria miniata as a model system to elucidate a shape-adaptation mechanism that robustly controls spatiotemporal protein dynamics on the membrane in spite of cell shape deformations. By combining experiments with biophysical theory, we show how cell shape information contained in a cytosolic gradient can be decoded by a bistable regulator of the enzyme Rho, which is associated with contractility. This bistable front in turn controls a mechanochemical response by locally triggering excitable dynamics of Rho. We posit that such a shape-adaptation mechanism based on a hierarchy of protein patterns may constitute a general physical principle for cell shape sensing and control.

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Fig. 1: Contraction waves in starfish oocytes confined in compartments with different geometries.
Fig. 2: The Cdk1–Ect2–Rho pattern hierarchy.
Fig. 3: Model of Rho dynamics.
Fig. 4: Model of Ect2 front regulation by the Cdk1-cyclinB gradient.

Data availability

All data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

Code availability

The code that supports the plots within this paper are described in the Methods and Supplementary Information and are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank P. Lenart, J. Bischof, K. Keren, A. Martin, A. Goryachev and E. Zanin for discussions. We also thank W. Salmon and staff at the W.M. Keck Microscopy Facility at the Whitehead Institute for microscopy support. E.F. acknowledges the hospitality of the Kavli Institute of Nanoscience at the Delft University of Technology where part of this work was done. This research was supported by a National Science Foundation CAREER award (to N.F.), a German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) fellowship within the Graduate School of Quantitative Biosciences Munich (to M.C.W.), the Joachim Herz Foundation (to M.C.W.), the DFG via B2 projects within the Collaborative Research Center SFB 1032 (to E.F.), and the DFG via the Research Training Group GRK 2062 (to F.B.). This research was supported in part by the National Science Foundation under grant no. NSF PHY-1748958.

Author information

Authors and Affiliations

Authors

Contributions

T.H.T. and N.F. initiated the project and designed the experiments. T.H.T. and J.L. performed the experiments and analysed the experimental data. M.C.W., F.B. and E.F. designed the model. M.C.W. performed the simulations and analysed the simulation data. S.Z.S. contributed reagents. All authors participated in interpreting the experimental and theoretical results and in writing the manuscript.

Corresponding authors

Correspondence to Erwin Frey or Nikta Fakhri.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Physics thanks Leah Edelstein-Keshet, Nicolas Minc and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–21, Tables 1 and 2, theoretical derivations and references.

Reporting Summary

Supplementary Video 1

Surface contraction wave of starfish oocyte during meiosis I. Rho-GTP is labelled fluorescently using rGBD-GFP reporter. Video taken with confocal microscopy at cross-section (left) and bottom plane (right) of oocytes. Time in min:s.

Supplementary Video 2

Rho-GTP wave (labelled with rGBD-GFP) of starfish oocyte during meiosis I when imaged in an elliptical PDMS chamber with AP at one corner. Video taken with confocal microscopy at cross-section of oocyte. Time in min:s.

Supplementary Video 3

Rho-GTP wave (labelled with rGBD-GFP) of starfish oocyte during meiosis I when imaged in an elliptical PDMS chamber with AP at side. Video taken with confocal microscopy at cross-section of oocyte. Time in min:s.

Supplementary Video 4

Rho-GTP wave (labelled with rGBD-GFP) of starfish oocyte during meiosis I when imaged in a triangular PDMS chamber with AP in the middle. Video taken with confocal microscopy at cross-section of oocyte. Time in min:s.

Supplementary Video 5

Rho-GTP wave (labelled with rGBD-GFP) of starfish oocyte during meiosis I when imaged in a star shape PDMS chamber with AP at one corner. Video taken with confocal microscopy at cross-section of oocyte. Time in min:s.

Supplementary Video 6

Spatiotemporal dynamics of Cdk1-cyclinB cytosolic gradient during meiosis I in starfish oocyte. The Cdk1 complex is imaged with cyclinB-GFP fluorescent reporter. Video taken with confocal microscopy at cross-section of oocyte. Time in min:s.

Supplementary Video 7

Spatiotemporal dynamics of Cdk1-cyclinB cytosolic gradient during meiosis I in starfish oocyte in ellipse with AP at one side. Video taken with confocal microscopy at cross-section of oocyte. Time in min:s.

Supplementary Video 8

Spatiotemporal dynamics of Cdk1-cyclinB cytosolic gradient during meiosis I in starfish oocyte in triangle with AP at one side. Video taken with confocal microscopy at cross-section of oocyte. Time in min:s.

Supplementary Video 9

Spatiotemporal dynamics of Cdk1-cyclinB cytosolic gradient during meiosis I in starfish oocyte in triangle with AP at one corner. Video taken with confocal microscopy at cross-section of oocyte. Time in min:s.

Supplementary Video 10

Dynamics of Rho-GTP spiral front at the oocyte membrane imaged using fluorescently labelled reporter rGBD-GFP. Time in min:s.

Supplementary Video 11

Ect2-mCherry front dynamics at the membrane. Owing to significant auto-fluorescent from cortex granules, we performed background subtraction by taking the cumulative sum of the fluorescent intensity difference (same procedure as for Ect2 space–time kymograph). The left video shows the raw data. The right video shows the background subtracted video. Note that the intensity around the periphery of oocyte in background subtracted video is due to the oocyte motion during surface contraction wave. Time in min:s.

Supplementary Video 12

Two-colour imaging of Ect2 (Ect2-mCherry fluorescent reporter) front and Rho-GTP (rGBD-GFP reporter) spiral front. Time in min:s.

Supplementary Video 13

Two-colour imaging of Cdk1-cyclinB (cyclinB-GFP fluorescent reporter) gradient and Ect2 (Ect2-mCherry fluorescent reporter) front. Time in min:s.

Supplementary Video 14

Simulation of the Rho model (see equations (1) and (2) in the Supplementary Information) on the surface of a spherical 3D volume using parameters for the wild type as specified in Supplementary Table 1.

Supplementary Video 15

Simulations of the Rho and Ect2 module in ellipsoidal 3D geometries. Left panel shows the Cdk1 concentration (log10(k[Cdk1])) in the cytoplasm and Rho-GTP (urt) on the membrane, and middle and right panels show the active Ect2 concentration (ue + uE) and the Rho-GTP concentration (urt) on the surface of the 3D geometry.

Supplementary Video 16

Simulations of the Rho and Ect2 module in triangular 3D geometries. Left panel shows the Cdk1 concentration (log10(k[Cdk1])) in the cytoplasm and Rho-GTP (urt) on the membrane, and middle and right panels show the active Ect2 concentration (ue + uE) and the Rho-GTP concentration (urt) on the surface of the 3D geometry

Supplementary Video 17

Simulations of the Rho and Ect2 module in star-shaped 3D geometries. Left panel shows the Cdk1 concentration (log10(k[Cdk1])) in the cytoplasm and Rho-GTP (urt) on the membrane, and middle and right panels show the active Ect2 concentration (ue + uE) and the Rho-GTP concentration (urt) on the surface of the 3D geometry.

Supplementary Video 18

Simulation of the Rho model (see equations (1) and (2) in the Supplementary Information) on the surface of a spherical 3D volume using parameters for Ect2 overexpression as specified in Supplementary Table 1.

Supplementary Video 19

Photoactivation experiment. Global light illumination at 488 nm begins at 0 s. Increase in yellow fluorescence indicates the recruitment of PR_GEF_YFP (photo-recruitable GEF labelled with yellow fluorescent protein) to the membrane. Beyond a certain threshold level, the oocyte contractility abruptly increases.

Supplementary Video 20

Maximal intensity projection of microtubule front near oocyte membrane during surface contraction wave imaged using ensconsin-GFP. Time in min:s.

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Wigbers, M.C., Tan, T.H., Brauns, F. et al. A hierarchy of protein patterns robustly decodes cell shape information. Nat. Phys. 17, 578–584 (2021). https://doi.org/10.1038/s41567-021-01164-9

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