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

• Type of Material: Article
• Authors: David Ellison, Johns Hopkins University; Andrew Mugler, Emory University; Matthew D. Brennan, Johns Hopkins University; Sung Hoon Lee, Yale University; Robert J. Huebner, Johns Hopkins University; Eliah R. Shamir, Johns Hopkins University; Laura A. Woo, Johns Hopkins University; Joseph Kim, Johns Hopkins University; Patrick Amar, Université Paris-Sud; Ilya Nemenman, Emory University; Andrew J. Ewald, Johns Hopkins University; Andre Levchenko, Yale University
• Language: English
• Date: 2016-02-09
• Publisher: National Academy of Sciences.
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2021 National Academy of Sciences
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1516503113
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 113
• Issue: 6
• Start Page: E679
• End Page: E688
• Grant/Funding Information: This work was supported in part by James S. McDonnell Foundation Grant 220020321 (to A.M. and I.N.); by National Science Foundation Grants 1410978 (to I.N.), 1410593 (to A.J.E.), and 1410545 (to A.L. and M.D.B.); by National Institutes of Health Grants GM072024 (to D.E., L.A.W., J.K., and A.L.), 2T32GM007445 (to R.J.H.), 3T32GM007309 (to N.M.N.), and CA15578 (to D.E., R.H., E.R.S., A.J.E., and A.L.); and by Semiconductor Research Corporation’s SemiSynBio program (S.H.L. and A.L.).
• Keywords: SINGLE; GENE-EXPRESSION; linear response theory; MAMMARY BRANCHING MORPHOGENESIS; EUKARYOTIC CHEMOTAXIS; chemotaxis; MOUSE; Science & Technology; MIGRATION; Science & Technology - Other Topics; FACTOR RECEPTOR; CANCER; collective cellular phenomena; GLAND DEVELOPMENT; gradient sensing; development; EPIDERMAL-GROWTH-FACTOR; Multidisciplinary Sciences
• Research Categories: Biology, Microbiology; Biology, Cell

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.