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

被引:116
作者
Ellison, David [1 ,2 ,3 ]
Mugler, Andrew [4 ,5 ]
Brennan, Matthew D. [1 ,2 ,3 ]
Lee, Sung Hoon [2 ,3 ]
Huebner, Robert J. [6 ,7 ]
Shamir, Eliah R. [6 ,7 ]
Woo, Laura A. [1 ]
Kim, Joseph [1 ]
Amar, Patrick [8 ]
Nemenman, Ilya [4 ,9 ]
Ewald, Andrew J. [6 ,7 ]
Levchenko, Andre [2 ,3 ]
机构
[1] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA
[2] Yale Univ, Dept Biomed Engn, New Haven, CT 06520 USA
[3] Yale Univ, Yale Syst Biol Inst, New Haven, CT 06520 USA
[4] Emory Univ, Dept Phys, Atlanta, GA 30322 USA
[5] Purdue Univ, Dept Phys & Astron, W Lafayette, IN 47907 USA
[6] Johns Hopkins Univ, Ctr Cell Dynam, Baltimore, MD 21205 USA
[7] Johns Hopkins Univ, Dept Cell Biol, Baltimore, MD 21205 USA
[8] Univ Paris 11, Bat 425, F-91405 Orsay, France
[9] Emory Univ, Dept Biol, Atlanta, GA 30322 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
gradient sensing; development; collective cellular phenomena; linear response theory; chemotaxis; MAMMARY BRANCHING MORPHOGENESIS; EPIDERMAL-GROWTH-FACTOR; GENE-EXPRESSION; EUKARYOTIC CHEMOTAXIS; GLAND DEVELOPMENT; FACTOR RECEPTOR; MIGRATION; CANCER; SINGLE; MOUSE;
D O I
10.1073/pnas.1516503113
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
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.
引用
收藏
页码:E679 / E688
页数:10
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