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Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis

David Ellison, Andrew Mugler, Matthew Brennan, Sung Hoon Lee, Robert Huebner, Eliah Shamir, Laura A. Woo, Joseph Kim, Patrick Amar, Ilya Nemenman, Andrew J. Ewald, Andre Levchenko
doi: https://doi.org/10.1101/025346
David Ellison
1Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
4Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT 06520, USA
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Andrew Mugler
2Department of Physics, Emory University, Atlanta, GA 30322, USA
3Department of Physics and Astronomy, Purdue University, West Lafayette, IN 47907, USA
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Matthew Brennan
1Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
4Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT 06520, USA
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Sung Hoon Lee
4Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT 06520, USA
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Robert Huebner
5Center for Cell Dynamics, Johns Hopkins University, Baltimore, MD 21205, USA
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Eliah Shamir
5Center for Cell Dynamics, Johns Hopkins University, Baltimore, MD 21205, USA
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Laura A. Woo
1Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
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Joseph Kim
1Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
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Patrick Amar
6Université Paris-Sud, 91405 ORSAY Cedex, France
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Ilya Nemenman
2Department of Physics, Emory University, Atlanta, GA 30322, USA
7Department of Biology, Emory University, Atlanta, GA 30322, USA
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  • For correspondence: ilya.nemenman@emory.edu andrew.ewald@jhmi.edu andre.levchenko@yale.edu
Andrew J. Ewald
5Center for Cell Dynamics, Johns Hopkins University, Baltimore, MD 21205, USA
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  • For correspondence: ilya.nemenman@emory.edu andrew.ewald@jhmi.edu andre.levchenko@yale.edu
Andre Levchenko
4Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT 06520, USA
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  • For correspondence: ilya.nemenman@emory.edu andrew.ewald@jhmi.edu andre.levchenko@yale.edu
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Abstract

Collective cell responses to exogenous cues depend on cell-cell interactions. In principle, these can result in enhanced sensitivity to weak and noisy stimuli. However, this has not yet been shown experimentally, and, little is known about how multicellular signal processing modulates single cell sensitivity to extracellular signaling inputs, including those guiding complex changes in the tissue form and function. Here we explored if cell-cell communication can enhance the ability of cell ensembles to sense and respond to weak gradients of chemotactic cues. Using a combination of experiments with mammary epithelial cells and mathematical modeling, we find that multicellular sensing enables detection of and response to shallow Epidermal Growth Factor (EGF) gradients that are undetectable by single cells. However, the advantage of this type of gradient sensing is limited by the noisiness of the signaling relay, necessary to integrate spatially distributed ligand concentration information. We calculate the fundamental sensory limits imposed by this communication noise and combine them with the experimental data to estimate the effective size of multicellular sensory groups involved in gradient sensing. Functional experiments strongly implicated intercellular communication through gap junctions and calcium release from intracellular stores as mediators of collective gradient sensing. The resulting integrative analysis provides a framework for understanding the advantages and limitations of sensory information processing by relays of chemically coupled cells.

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Posted August 23, 2015.
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Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis
David Ellison, Andrew Mugler, Matthew Brennan, Sung Hoon Lee, Robert Huebner, Eliah Shamir, Laura A. Woo, Joseph Kim, Patrick Amar, Ilya Nemenman, Andrew J. Ewald, Andre Levchenko
bioRxiv 025346; doi: https://doi.org/10.1101/025346
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Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis
David Ellison, Andrew Mugler, Matthew Brennan, Sung Hoon Lee, Robert Huebner, Eliah Shamir, Laura A. Woo, Joseph Kim, Patrick Amar, Ilya Nemenman, Andrew J. Ewald, Andre Levchenko
bioRxiv 025346; doi: https://doi.org/10.1101/025346

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