A mass of migrating cells in the zebrafish embryo keep to one direction by vacuuming up the path behind them. Credit: EMBL/E. Donà
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In a nutshell:
Zebrafish embryo’s cells can move in one direction by creating their own gradient
Could have implications for cancer and metastasis
Discovered using a tag that changes colour as its target ages
Migrating cells, it seems, cover their tracks not for fear of being followed, but to keep moving forward. Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have now shown that cells in a zebrafish embryo determine which direction they move in by effectively erasing the path behind them. The findings, published online today in Nature, could have implications not just for development but also for cancer and metastasis.
As a zebrafish embryo develops, a group of cells migrate down the side of its body, leaving clumps of cells along the way. Those clumps will become ear-like organs, sensing vibrations in the water. In the adult fish, this is called the lateral line, so the moving mass in the embryo is dubbed the lateral line primordium. To migrate, these cells follow a trail of a molecule called a chemokine – but how do they know to keep moving in the same direction? Scientists assumed that the trail was a one-way path: a gradient where cells moved from less- to more-concentrated chemokine. But Darren Gilmour and colleagues at EMBL have now found that, rather than being produced outside them, that gradient is actually generated by the cells themselves.
“We found that the cells at the rear of the group have a ‘vacuum cleaner’,” says Erika Donà, who carried out the work. “They suck up the chemokine at the back, but at the front there’s still a lot of chemokine to follow, so the cells move forward.”
To investigate the role of the ‘vacuum cleaner’ molecule, Gilmour and Donà turned to a ‘detector’ molecule which all cells in the primordium use to sniff out the chemokine, and which the scientists labelled with a tag that goes from green to red as the detector ages.
Video 1: Zebrafish lateral line migration: painting by age
Cells at the front of the primordium glowed green, showing they were in such frequent contact with the chemokine that their detectors were constantly being renewed, while cells at the rear encountered so little chemokine that their detectors had a chance to grow old, painting the cells red. To show that this gradient is created by the act of sucking up the chemokine, the scientists genetically engineered fish to have the vacuum cleaner molecule in an accompanying nerve rather than at the rear of the primordium itself. When the vacuum cleaner was switched to the nerve, the nerve went from following the migrating primordium to guiding it.
Video 2: Zebrafish lateral line migration: One direction
“It makes a lot of sense for the cells to choose their own direction,” says Darren Gilmour, who led the work. “There’s a lot going on in the embryo, lots of cells moving in lots of directions, so it may be very difficult to sustain a gradient. What we’ve shown is that you don’t always need to.”
The study could also be relevant to another, seemingly very different type of moving cells: those in metastasising cancers. Scientists have found that both the ‘detector’ and the ‘vacuum cleaner’ molecule play important roles in different tumours’ ability to metastasise – to spread from one place to another in the body. These findings hint at what those roles might be, and consequently at possible ways to block them.
The colour-changing tag used in this study was first developed by Anton Khmelinskii in the group of EMBL Alumnus Michael Knop, now at the DKFZ-ZMBH Alliance. Joseph Barry in the Huber group helped develop and apply data analysis methods for this work.
Doná, E., Barry, J.D., Valentin, G., Quirin, C., Khmelinskii, A., Kunze, A., Durdu, S., Newton, L.R., Fernandez-Minan, A., Huber, W., Knop, M. & Gilmour, D. Directional Tissue Migration Through a Self-Generated Chemokine Gradient. Published online in Nature on 25 September 2013. DOI: 10.1038/nature12635.
The directed migration of cell collectives is a driving force of embryogenesis. 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 them, a strategy that potentially allows self- determined directionality. However, a lack of tools for the visualisation 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 demonstrate that migrating cell collectives can self-generate gradients of chemokine activity across their length via polarised receptor-mediated internalisation. 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 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 invasion.
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