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Directional tissue migration through a self-generated chemokine gradient
Erika Dona，Joseph D. Barry，Guillaume Valentin，Charlotte Quirin，Anton Khmelinskii，Andreas Kunze，Sevi Durdu，Lionel R. Newton，Ana Fernandez-Minan，Wolfgang Huber，Michael Knop& Darren Gilmour
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.
