Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Feb 9;113(6):E679-88. doi: 10.1073/pnas.1516503113. Epub 2016 Jan 20.

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

Author information

1
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;
2
Department of Physics, Emory University, Atlanta, GA 30322; Department of Physics and Astronomy, Purdue University, West Lafayette, IN 47907;
3
Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT 06520;
4
Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University, Baltimore, MD 21205;
5
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218;
6
Université Paris-Sud, 91405 ORSAY Cedex, France;
7
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.
8
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.
9
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.

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.

KEYWORDS:

chemotaxis; collective cellular phenomena; development; gradient sensing; linear response theory

Comment in

PMID:
26792522
PMCID:
PMC4760786
DOI:
10.1073/pnas.1516503113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center