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Mechanisms and in vivo functions of contact inhibition of locomotion

Nature Reviews Molecular Cell Biology volume 18, pages 43–55 (2017)Cite this article

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Key Points

  • The process of contact inhibition of locomotion (CIL) has been observed in a wide range of migrating cell types in vitro. CIL encompasses a range of different overall behaviours, from simple cessation of migration to complete repolarization; however, it is likely that common regulatory mechanisms exist among these behaviours.

  • A prototypical CIL response involves a series of distinct stages, including cell–cell adhesion, modulation of cytoskeletal dynamics and finally cell repolarization. These steps are regulated by mechano-chemical signals, which must be integrated to induce a seamless response.

  • Numerous mathematical models that incorporate CIL have revealed that it can lead to emergent cellular behaviours, from cell patterning to collective motion.

  • Since the 1950s, CIL has primarily been studied in vitro. However, recent work revealed its requirement during several developmental processes, such as neuronal cell dispersion, macrophage distribution and the collective migration of neural crest cells.

  • CIL and its regulation are likely to be important for many other physiological processes and has been implicated in pathologies such as cancer metastasis.

Abstract

Contact inhibition of locomotion (CIL) is a process whereby a cell ceases motility or changes its trajectory upon collision with another cell. CIL was initially characterized more than half a century ago and became a widely studied model system to understand how cells migrate and dynamically interact. Although CIL fell from interest for several decades, the scientific community has recently rediscovered this process. We are now beginning to understand the precise steps of this complex behaviour and to elucidate its regulatory components, including receptors, polarity proteins and cytoskeletal elements. Furthermore, this process is no longer just in vitro phenomenology; we now know from several different in vivo models that CIL is essential for embryogenesis and in governing behaviours such as cell dispersion, boundary formation and collective cell migration. In addition, changes in CIL responses have been associated with other physiological processes, such as cancer cell dissemination during metastasis.

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Figure 1: Types of contact inhibition of locomotion behaviours and their outcomes.
Figure 2: Stages of contact inhibition of locomotion and their regulatory mechanisms.
Figure 3: Cadherin switching in the regulation of epithelial–mesenchymal transition and contact inhibition of locomotion.
Figure 4: Embryological functions of contact inhibition of locomotion.
Figure 5: Unexplored roles for contact inhibition of locomotion.

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Acknowledgements

The authors thank G. Jones, C. Linker and M. Parsons for their comments on the manuscript. B.S. is supported by the Wellcome Trust and the European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement number 68108). R.M. is supported by the Medical Research Council and the Biotechnology and Biological Sciences Research Council.

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  1. Randall Division of Cell and Molecular Biophysics, King's College London, London, SE1 1UL, UK

    Brian Stramer

  2. Cell and Developmental Biology Department, University College London, London, WC1E 6BT, UK

    Roberto Mayor

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Supplementary information

Supplementary information S1 (movie)

Movies from the Abercrombie laboratory showing events of contact inhibition of locomotion (CIL) between chick heart fibroblasts, which is an example of a cell type exhibiting Type I CIL behaviour. The low magnification view highlights the collision and subsequent migration away from the colliding partner, while the high magnification view shows the sudden recoil of colliding lamellae, suggesting the buildup and release of tension. Movies were restored and digitized with the help of the Wellcome Library (http://blog.wellcomelibrary.org/2014/09/cells-on-film-making-movies-in-biology/)1 (MP4 12253 kb)

1. Stramer, B.M. & Dunn, G.A. Cells on film - the past and future of cinemicroscopy. J Cell Sci 128, 9–13 (2015).

Supplementary information S2 (movie)

Timelapse movie of Drosophila melanogaster macrophages (haemocytes) undergoing contact inhibition of locomotion (CIL) and developmentally dispersing within the embryo. Haemocytes contain fluorescently labelled microtubules along with a nuclear marker, which allows for automated tracking of cells. A single macrophage was tracked in the centre of the field, which revealed sudden reversals in direction upon collision with neighbouring cells and this repulsion is suggestive of Type I CIL behaviour. Note the relatively even spreading of cells within the field of view, which is controlled by CIL dynamics1,2,3. (MP4 2481 kb)

1. Davis, J.R. et al. Inter-cellular forces orchestrate contact inhibition of locomotion. Cell 161, 361–73 (2015).

2. Davis, J.R. et al. Emergence of embryonic pattern through contact inhibition of locomotion. Development 139, 4555–60 (2012).

3. Stramer, B. et al. Clasp-mediated microtubule bundling regulates persistent motility and contact repulsion in Drosophila macrophages in vivo. J Cell Biol 189, 681–9 (2010).

Supplementary information S3 (movie)

Movies from the Abercrombie laboratory showing events of contact inhibition of locomotion (CIL) between epithelial cells in culture. The low magnification view highlights the collision of two epithelial sheets in culture, while the high magnification view shows epithelial cell collision between dispersed cells. Epithelial cells do not show active repolarization during CIL, which is suggestive of Type II CIL behaviour. Movies were restored and digitized with the help of the Wellcome Library (http://blog.wellcomelibrary.org/2014/09/cells-on-film-making-movies-in-biology/)1. (MP4 14966 kb)

1. Stramer, B.M. & Dunn, G.A. Cells on film - the past and future of cinemicroscopy. J Cell Sci 128, 9–13 (2015).

Supplementary information S4 (movie)

Movies from the Abercrombie laboratory showing a loss of contact inhibition of locomotion (CIL) between S180 cells (sarcoma cells) and fibroblasts. Note that S-180 cells show a complete failure of CIL behaviour towards fibroblasts and are capable of using these cells as a substrate for their motility. In contrast, S180 cells still show CIL towards each other revealing a maintenance of homotypic CIL despite losing heterotypic CIL towards fibroblasts. Movies were restored and digitized with the help of the Wellcome Library (http://blog.wellcomelibrary.org/2014/09/cells-on-film-making-movies-in-biology/)1. (MP4 8508 kb)

1. Stramer, B.M. & Dunn, G.A. Cells on film - the past and future of cinemicroscopy. J Cell Sci 128, 9–13 (2015).

Supplementary information S5 (movie)

Simulation of outgrowth of an explant of cells in culture. Left panel shows cell positions, while right panel shows cell tracks. Cells were assumed to migrate with a biased random walk behaviour. However, when within a defined distance to a neighbouring cell, contact inhibition of locomotion ccurs leading to repulsion. These simple rules lead to spreading and radial outgrowth of simulated cells from the explant, which is similar to the behaviour of real explants in vitro. The precise parameters for this simulation were taken from mathematical modelling of dispersing Drosophila melanogaster macrophages1. (MP4 1059 kb)

1. Davis, J.R. et al. Emergence of embryonic pattern through contact inhibition of locomotion. Development 139, 4555–60 (2012).

PowerPoint slides

Glossary

Leading edge

This term is used synonymously with lamellae here and describes the front of a migrating cell that contains an actin network that pushes out the plasma membrane, which is involved in generating the forces underlying cell migration.

Adherens junction

A cadherin-mediated cell–cell junction that is normally thought to mediate stable adhesion between epithelial cells.

Neural crest cells

A transient, vertebrate-specific embryonic cell population originating from the neural ectoderm, which undergoes a number of developmental migratory behaviours before differentiating into diverse cell types, such as melanocytes, cartilage and glia.

Epithelial–mesenchymal transition

(EMT). A process by which epithelial cells lose epithelial characteristics, such as their polarity and cell–cell adhesions, and gain characteristics thought to be specific to mesenchymal cells, such as enhanced motility and invasiveness.

Eph–ephrin interactions

Interactions between a transmembrane receptor (Eph) and its membrane-bound ligand (ephrin), which can signal bidirectionally (that is, both receptor and ligand can induce intracellular signalling) to control behaviours such as cell repulsion.

Cajal–Retzius cells

A transient neuronal population established during embryogenesis that undergoes specific migration and spreading in the cortex of the brain, which controls the development of other neuronal cells.

SLIT–ROBO

A transmembrane receptor (ROBO) and its normally secreted ligand (SLIT) largely studied in the context of neuronal growth cone guidance.

Small GTPases

A family of proteins that includes RHO, RAC and CDC42, which are involved in the regulation of the cytoskeleton.

Planar cell polarity

(PCP). The polarization of cells within a sheet in a planar fashion, which involves a core set of components involving transmembrane proteins, such as Frizzled, and downstream signalling mediators, such as Dishevelled.

Glial cells

Cells supporting neuronal development and function in the central nervous system.

Formin

A family of proteins involved in polymerization of actin, which has been shown to regulate specific actin structures, and the organization of contractile cytoskeletal elements in cells such as stress fibres.

Microtubule catastrophe

The transition of a microtubule from a growth to a shortening phase.

Substrate traction stresses

Cells residing on elastic substrates will pull on the substrate and produce fine-scale deformations, which can be measured to estimate the stress that the cells exert on their extracellular matrix.

Focal adhesions

Specific adhesions that anchor cells to the substrate; they contain a complex of signalling proteins, such as focal adhesion kinase and paxillin, along with transmembrane proteins such as integrins.

Interference reflection microscopy

A microscopy technique for cells cultured in vitro that uses polarized light to highlight cell structures close to the substrate. This technique was first used to highlight points of cell–substrate adhesion (focal adhesions).

Collective cell migration

A process whereby a collection of cells engages in coordinated motility such that they move as a coherent group.

Chemotaxis

The response of cells to an extracellular chemical signal, which induces their migration in a directed fashion.

Neuronal growth cones

Dynamic, actin-rich structures at the termini of axons that control the migration of nerve cells.

Dendritic fields

The development of an array of neuronal processes called dendrites in which individual cells cover specific, non-overlapping spatial territories.

Mesenchymal cells

Cells of embryonic origin that exist in connective tissues throughout the body and develop into a broad range of cell types, such as cartilage and bone.

Immune cell swarming

A process whereby collections of white blood cells, such as neutrophils, become activated and show coordinated chemotaxis and cluster formation, which is reminiscent of the swarming behaviour of insects.

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Stramer, B., Mayor, R. Mechanisms and in vivo functions of contact inhibition of locomotion. Nat Rev Mol Cell Biol 18, 43–55 (2017). https://doi.org/10.1038/nrm.2016.118

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