Directional tissue migration through a self-generated chemokine gradient
| Autor: | Erika Donà, Anton Khmelinskii, Lionel R. Newton, Charlotte Quirin, Sevi Durdu, Joseph Barry, Darren Gilmour, Guillaume Valentin, Michael Knop, Andreas Kunze, Ana Fernandez-Minan, Wolfgang Huber |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Nature. 503:285-289 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature12635 |
| Popis: | It is widely accepted that migrating cells and tissues navigate along pre-patterned chemoattractant gradients; here it is shown that migrating tissues can also determine their own direction by generating local gradients of chemokine activity, via polarized receptor-mediated internalization, that are sufficient to ensure robust collective migration. The currently accepted view of how cells migrate directionally over long distances — an important driving force in embryogenesis — is that they navigate using pre-patterned chemoattractant guidance gradients. In this study Darren Gilmour and colleagues present the first in vivo evidence for a rather different mechanism: self-generated guidance gradient formation. Using zebrafish lateral line primordium as a model for collective cell migration, the authors show that migrating tissues can determine their own direction by generating local gradients in initially uniform extracellular guidance cues, producing a travelling wave. The atypical chemokine receptor Cxcr7 is the key regulator of the process, being both necessary and sufficient for self-directed migration. The finding that cells can autonomously determine their migration routes could have wider implications in processes such as cancer metastasis. The directed migration of cell collectives is a driving force of embryogenesis1,2,3. The predominant view in the field is that cells in embryos navigate along pre-patterned chemoattractant gradients2. One hypothetical way to free migrating collectives from the requirement of long-range gradients would be through the self-generation of local gradients that travel with them4,5, a strategy that potentially allows self-determined directionality. However, a lack of tools for the visualization of endogenous guidance cues has prevented the demonstration of such self-generated gradients in vivo. Here we define the in vivo dynamics of one key guidance molecule, the chemokine Cxcl12a, by applying a fluorescent timer approach to measure ligand-triggered receptor turnover in living animals. Using the zebrafish lateral line primordium as a model, we show that migrating cell collectives can self-generate gradients of chemokine activity across their length via polarized receptor-mediated internalization. Finally, by engineering an external source of the atypical receptor Cxcr7 that moves with the primordium, we show that a self-generated gradient mechanism is sufficient to direct robust collective migration. This study thus provides, to our knowledge, the first in vivo proof for self-directed tissue migration through local shaping of an extracellular cue and provides a framework for investigating self-directed migration in many other contexts including cancer invasion6. |
| Databáze: | OpenAIRE |
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