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Changing directions in the study of chemotaxis

Key Points

  • The guidance strategy of a cell varies with the chemotactic gradient: in steep gradients, cells produce pseudopodia directly up the gradient, but in weak gradients, pseudopodia are produced at random, with cells steering by favouring the pseudopod that is furthest up the gradient. Cells can also become polarized such that they maintain the same front end, even when forced to change direction by a changing gradient.

  • Chemotactic gradients cause Dictyostelium amoebae and neutrophils to produce aligned gradients of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) in their plasma membranes. Genetic experiments that ablate the PtdIns(3,4,5)P3 kinases and the PtdIns(3,4,5)P3 phosphatases that are producing these gradients show that gradients are important for basic cell motility and chemotaxis in weak gradients, but are not essential for chemotaxis in strong gradients.

  • Genetic experiments suggest that Dictyostelium chemotactic signalling to cyclic AMP (cAMP) is channelled through redundant Ras proteins that activate phosphatidylinositol 3-kinases and the target of rapamycin complex-2 (TORC2) in parallel and, eventually, cyclic GMP production. Phospholipase A2 is also activated by cAMP and is important for chemotaxis.

  • The leading edge is extended partially by the force of dendritic actin polymerization beneath the membrane, but also, possibly, by the collision of travelling filamentous-actin waves with the membrane.

  • Hydrostatic pressure contributes to the movement of various cell types, providing an alternative force for extending the leading edge. Hydrostatic pressure tends to produce blebs and is dependent on myosin II.

  • Moving cells may have to regulate their surface area as they change shape and, because the plasma membrane is mostly inextensible, this might require an intimate coordination of movement with the endocytic cycle.

Abstract

Chemotaxis — the guided movement of cells in chemical gradients — probably first emerged in our single-celled ancestors and even today is recognizably similar in neutrophils and amoebae. Chemotaxis enables immune cells to reach sites of infection, allows wounds to heal and is crucial for forming embryonic patterns. Furthermore, the manipulation of chemotaxis may help to alleviate disease states, including the metastasis of cancer cells. This review discusses recent results concerning how cells orientate in chemotactic gradients and the role of phosphatidylinositol-3,4,5-trisphosphate, what produces the force for projecting pseudopodia and a new role for the endocytic cycle in movement.

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Figure 1: Behaviour of Dictyostelium cells in gradients.
Figure 2: A simplified version of the upper part of the Dictyostelium chemotactic pathway for cyclic AMP.
Figure 3: PtdIns(3,4,5)P3 gradients are not required for chemotaxis.
Figure 4: F-actin waves.
Figure 5: Three-dimensional reconstructions of a Dictyostelium cell that is undergoing chemotaxis towards cAMP.

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Acknowledgements

We would like to thank M. Bretscher for stimulating our interest in cell motility and the anonymous reviewers and many others for discussion.

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Correspondence to Robert R. Kay.

Supplementary information

Supplementary information S1 (movie)| Dictyostelium cells navigating by splitting their pseudopodia and supporting the better-orientated daughter.

Reproduced with permission from Ref. 1. (MOV 733 kb)

41580_2008_BFnrm2419_MOESM3_ESM.pdf

Supplementary information S2 (movie)| Dictyostelium cells chemotaxing to a needle releasing cyclic AMP.

Note highly elongated cells and their tendency to make head-to-tail connections. Reproduced with permission from Ref 1. (MOV 28 kb)

41580_2008_BFnrm2419_MOESM5_ESM.pdf

Supplementary information S3 (movie)| Chemotaxis of Dictyostelium PI3K1-5-/PTEN sextuple mutant cells to a needle releasing cyclic AMP.

Reproduced with permission from Ref. 1. (MOV 185 kb)

41580_2008_BFnrm2419_MOESM7_ESM.pdf

Supplementary information S4 (movie)| Waves of actin polymerization on the basal membrane of Dictyostelium cells, visualized using TIRF microscopy and an F-actin binding protein reporter (mRFP–limE–Delta after latrunculin washout).

Movie courtesy of Till Bretschneider and Gunther Gerisch. (MOV 2491 kb)

41580_2008_BFnrm2419_MOESM9_ESM.pdf

Supplementary information S5 (movie)| Hem1–yellow fluorescent protein (YFP) waves in neutrophil-like HL60 cells, uniformly exposed to 20 nM fMLP.

Hem is a component of the Scar/WAVE complex and initially concentrates in foci, which form outwardly propagating waves that eventually develop into a polarized accumulation of Hem1 at the leading edge. Cell morphology precisely corresponds with the distribution of the most peripheral waves. Reproduced from Ref. 1. (MOV 2473 kb)

41580_2008_BFnrm2419_MOESM11_ESM.pdf

Supplementary information S6 (movie)| Blebbing motility of zebra fish primordial germ cells, showing distribution of enhanced green fluorescent protein (EGFP)–actin.

Reproduced with permission from Ref. 1. (MOV 1362 kb)

41580_2008_BFnrm2419_MOESM13_ESM.pdf

Supplementary information S7 (movie)| Blebbing motility of zebra fish primordial germ cells expressing an enhanced green fluorescent protein (EGFP) plasma membrane marker.

Reproduced with permission from REF. 1. (MOV 4874 kb)

41580_2008_BFnrm2419_MOESM15_ESM.pdf

Supplementary information S8 (movie)| Three-dimensional reconstruction of a chemotaxing Dictyostelium cell expressing a fluorescent surface marker (cAMP receptor-1 (cAR1)–GFP) and examined by confocal microscopy.

Illustrates dramatic changes in shape and hence in surface area. (MOV 63 kb)

41580_2008_BFnrm2419_MOESM17_ESM.pdf

Supplementary information S9 (movie)| Paralysis of Dictyostelium nsfA2 cells at the restrictive temperature, where the block in the endocytic cycle somehow prevents most cells from moving towards a needle releasing cyclic AMP.

Reproduced with permission from Ref. 1. (MOV 15363 kb)

41580_2008_BFnrm2419_MOESM19_ESM.pdf

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FURTHER INFORMATION

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Glossary

Pseudopod

An organelle-free projection that is thicker than other types of cell projection. Pseudopodia contain filamentous actin and are formed by cells such as amoebae.

Substratum

The surface on which cells move. The nature of the substratum can change the behaviour of cells.

Lamellipodium

A thin, organelle-free projection that contains filamentous actin. Lamellipodia are formed by cells such as fibroblasts or keratocytes.

Leading edge

The front of the cell.

PtdIns(3,4,5)P3

A signalling phospholipid and minor component of the plasma membrane that serves as a binding site for proteins that contain specific pleckstrin-homology domains.

Dictyostelium type-I PI3Ks

The domain organization of these proteins resembles mammalian type-I phosphatidylinositol 3-kinases, especially because they have a Ras-binding domain.

Chemotactic index

A measure of the accuracy of chemotaxis that is calculated by taking the cosine of the angle between a line directly up the gradient and one that connects a cell's start point to its end point. A value of 1 is directly up the gradient.

Hydrostatic pressure

A force that is applied by fluid to any surface it is in contact with. Hydrostatic pressure allows forces that are produced by the contraction of the back of a cell to be transmitted to the front.

Photobleaching

The bleaching of fluorophores, such as green fluorescent protein, by light of sufficient intensity. Photobleaching can be used to create small bleached spots on the structure of interest, the movement of which can then be monitored.

Speckle microscopy

A technique in which nearly all of the chromophores in a structrure, such as actin–green fluorescent protein that has been polymerized into filamentous actin, are photobleached such that those that remain can be tracked individually as speckles.

HL60 cells

Human leukaemia cells that can be induced to differentiate into motile neutrophil-like cells.

SNARE complexes

(soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor complexes). Proteins that are required for the fusion of membrane vesicles. They form a complex during fusion that has to be resolved before they can be reused.

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Kay, R., Langridge, P., Traynor, D. et al. Changing directions in the study of chemotaxis. Nat Rev Mol Cell Biol 9, 455–463 (2008). https://doi.org/10.1038/nrm2419

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