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

David Ellison, Andrew Mugler, Matthew D. Brennan, Sung Hoon Lee, Robert J. Huebner, Eliah R. Shamir, Laura A. Woo, Joseph Kim, Patrick Amar, Ilya Nemenman, Andrew J. Ewald, Andre Levchenko

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)E679-E688
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number6
DOIs
StatePublished - Feb 9 2016

Keywords

  • Chemotaxis
  • Collective cellular phenomena
  • Development
  • Gradient sensing
  • Linear response theory

ASJC Scopus subject areas

  • General

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