Competition between chemoattractants causes unexpected complexity and can explain negative chemotaxis

Dowdell, A., Paschke, P. I., Thomason, P. A., Tweedy, L. and Insall, R. H. (2023) Competition between chemoattractants causes unexpected complexity and can explain negative chemotaxis. Current Biology, 32(9), 1704-1715.e3. (doi: 10.1016/j.cub.2023.03.006) (PMID:37001521)

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Abstract

Negative chemotaxis, where eukaryotic cells migrate away from repellents, is important throughout biology, for example, in nervous system patterning and resolution of inflammation. However, the mechanisms by which molecules repel migrating cells are unknown. Here, we use predictive modeling and experiments with Dictyostelium cells to show that competition between different ligands that bind to the same receptor leads to effective chemorepulsion. 8-CPT-cAMP, widely described as a simple chemorepellent, is inactive on its own and only repels cells when it acts in combination with the attractant cAMP. If cells degrade either competing ligand, the pattern of migration becomes more complex; cells may be repelled in one part of a gradient but attracted elsewhere, leading to populations moving in different directions in the same assay or converging in an arbitrary place. More counterintuitively still, two chemicals that normally attract cells can become repellent when combined. Computational models of chemotaxis are now accurate enough to predict phenomena that have not been anticipated by experiments. We have used them to identify new mechanisms that drive reverse chemotaxis, which we have confirmed through experiments with real cells. These findings are important whenever multiple ligands compete for the same receptors.

Item Type:Articles
Additional Information:The authors are grateful to Cancer Research UK (CRUK) for core funding to the CRUK Beatson Institute (A31287) and to R.H.I. (A19257), and to the Wellcome Trust for grant 221786/Z/20/Z to R.H.I.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tweedy, Dr Luke and Insall, Professor Robert and Thomason, Dr Peter and Dowdell, Adam and Paschke, Dr Peggy
Authors: Dowdell, A., Paschke, P. I., Thomason, P. A., Tweedy, L., and Insall, R. H.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Current Biology
Publisher:Elsevier (Cell Press)
ISSN:0960-9822
ISSN (Online):1879-0445
Published Online:30 March 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Current Biology 33(9): 1704-1715.e3
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
311739Resubmission: Understanding The Physiology Of Chemotaxis Towards Self-Generated Gradients, using Models, Model Organisms and T cellsRobert InsallWellcome Trust (WELLCOTR)221786/Z/20/ZInstitute of Cancer Sciences