title: Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis.
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 whether 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.
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218; Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT 06520;
authors.forename: David
authors.initials: D
authors.lastname: Ellison
authors.affiliation: Department of Physics, Emory University, Atlanta, GA 30322; Department of Physics and Astronomy, Purdue University, West Lafayette, IN 47907;
authors.forename: Andrew
authors.initials: A
authors.lastname: Mugler
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218; Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT 06520;
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Brennan
authors.affiliation: Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT 06520;
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University, Baltimore, MD 21205;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Huebner
authors.affiliation: Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University, Baltimore, MD 21205;
authors.forename: Eliah R
authors.initials: ER
authors.lastname: Shamir
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218;
authors.forename: Laura A
authors.initials: LA
authors.lastname: Woo
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218;
authors.forename: Joseph
authors.initials: J
authors.lastname: Kim
authors.affiliation: Université Paris-Sud, 91405 ORSAY Cedex, France;
authors.forename: Patrick
authors.initials: P
authors.lastname: Amar
authors.affiliation: Department of Physics, Emory University, Atlanta, GA 30322; Department of Biology, Emory University, Atlanta, GA 30322 andre.levchenko@yale.edu ilya.nemenman@emory.edu andrew.ewald@jhmi.edu.
authors.forename: Ilya
authors.initials: I
authors.lastname: Nemenman
authors.affiliation: Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University, Baltimore, MD 21205; andre.levchenko@yale.edu ilya.nemenman@emory.edu andrew.ewald@jhmi.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ewald
authors.affiliation: Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT 06520; andre.levchenko@yale.edu ilya.nemenman@emory.edu andrew.ewald@jhmi.edu.
authors.forename: Andre
authors.initials: A
authors.lastname: Levchenko
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003198:Computer Simulation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D007477:Ions; D008024:Ligands; D008321:Mammary Glands, Animal / Q000166:cytology; D008954:Models, Biological; D009024:Morphogenesis / Q000187:drug effects; D009940:Organoids / Q000166:cytology / Q000187:drug effects; D051381:Rats; D013997:Time Factors
chemical_list: D015820:Cadherins; D007477:Ions; D008024:Ligands; D004815:Epidermal Growth Factor; D002118:Calcium
keywords: chemotaxis; collective cellular phenomena; development; gradient sensing; linear response theory