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Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding

Abstract

The development and maintenance of an epithelium requires finely balanced rates of growth and cell death. However, the mechanical and biochemical mechanisms that ensure proper feedback control of tissue growth1,2,3,4, which when deregulated contribute to tumorigenesis, are poorly understood. Here we use the fly notum as a model system5 to identify a novel process of crowding-induced cell delamination that balances growth to ensure the development of well-ordered cell packing. In crowded regions of the tissue, a proportion of cells undergo a serial loss of cell–cell junctions and a progressive loss of apical area, before being squeezed out by their neighbours. This path of delamination is recapitulated by a simple computational model of epithelial mechanics, in which stochastic cell loss relieves overcrowding as the system tends towards equilibrium. We show that this process of delamination is mechanistically distinct from apoptosis-mediated cell extrusion6,7,8 and precedes the first signs of cell death. Overall, this analysis reveals a simple mechanism that buffers epithelia against variations in growth. Because live-cell delamination constitutes a mechanistic link between epithelial hyperplasia and cell invasion, this is likely to have important implications for our understanding of the early stages of cancer development.

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Figure 1: Stochastic cell delamination from crowded regions of a tissue during normal development.
Figure 2: Delamination counter-balances tissue growth.
Figure 3: Topological rearrangements drive a stochastic process of delamination in overcrowded tissues.
Figure 4: Crowding-induced delamination is a cause not a consequence of cell death and is distinct from apoptosis-mediated extrusion.

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Acknowledgements

We thank J. Rosenblatt for communicating results before publication; N. Tapon, F. Pichaud, G. Charras and J. Rohn for helpful comments on the text; and the members of the Baum laboratory, in particular K. Van Hegan, J. Bellis and J. Beira. B.B. and E.M. thank Cancer Research UK for funding. B.B. also thanks University College London, Wellcome and the Royal Society for financial support.

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Authors and Affiliations

Authors

Contributions

E.M. conducted the experiments detailed in the paper, aided by S.C. The laser ablation work was done with technical assistance from J.G. A.M. performed the theoretical analysis. T.D. oversaw the theoretical analysis. B.B. oversaw the experimental work.

Corresponding author

Correspondence to Buzz Baum.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text, Supplementary Table 1 and Supplementary Figures 1-13. (PDF 14326 kb)

Supplementary Movie

This movie shows developing notum visualized with E-Cadherin::GFP. The movie covers the period 14-26h AP, during which cells delaminate as indicated in Figure 1. Total time is 740 minutes, with frames at 10 minute intervals. (MOV 1626 kb)

Supplementary Movie

This movie shows developing notum visualized with E-Cadherin::GFP, expressing p110 PI3K driven by the pnr-Gal4 driver. Cells delaminate during this time interval (indicated in Figure 2). Time interval between frames is 10 minutes and the video length is 650 minutes. (MOV 7618 kb)

Supplementary Movie

This movie shows developing notum visualized with E-Cadherin::GFP, expressing Tsc1 and Tsc2 driven by the pnr-Gal4 driver. Cells delaminate during this time interval (indicated in Figure 2). Time interval between acquired frames is 10 minutes and the video length is 670 minutes. (MOV 1029 kb)

Supplementary Movie

This movie shows developing notum visualized with E-Cadherin::GFP, expressing dsRNA targeting Rbp5S driven from the pnr-Gal4 driver. Cells delaminate during this time interval. Time interval between frames is 10 minutes and the video length is 770 minutes. (MOV 3134 kb)

Supplementary Movie

This movie shows developing notum visualized with E-Cadherin::GFP, expressing dsRNA targeting Cdc25 driven from the pnr-Gal4 driver. Cells do not divide but delaminate during this time interval (indicated in Figure S3). Time interval between acquired frames is 5 minutes and the video length is 135 minutes. (MOV 124 kb)

Supplementary Movie

This movie shows developing notum visualized with E-Cadherin::GFP, expressing DIAP1 driven from the pnr-Gal4 driver. Cells delaminate during this time interval (indicated in Fig. 4). Time interval between frames is 10 minutes and the video length is 730 minutes. (MOV 1767 kb)

Supplementary Movie

The movie shows the simulation of tissue evolution with parameters corresponding to the wildtype midline tissue, when the geometry is elongated and the tissue is compressed (γ=2). It corresponds to the ‘wildtype’ case in Figure 3B. Cells are shaded according to the number of neighbors – lighter shades correspond to fewer neighbours. (MOV 1423 kb)

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Marinari, E., Mehonic, A., Curran, S. et al. Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding. Nature 484, 542–545 (2012). https://doi.org/10.1038/nature10984

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