Dynamic Buffering of Extracellular Chemokine by a Dedicated Scavenger Pathway Enables Robust Adaptation during Directed Tissue Migration

How tissues migrate robustly through changing guidance landscapes is poorly understood. Here, quantitative imaging is combined with inducible perturbation experiments to investigate the mechanisms that ensure robust tissue migration in vivo. We show that tissues exposed to acute “chemokine floods” halt transiently before they perfectly adapt, i.e., return to the baseline migration behavior in the continued presence of elevated chemokine levels. A chemokine-triggered phosphorylation of the atypical chemokine receptor Cxcr7b reroutes it from constitutive ubiquitination-regulated degradation to plasma membrane recycling, thus coupling scavenging capacity to extracellular chemokine levels. Finally, tissues expressing phosphorylation-deficient Cxcr7b migrate normally in the presence of physiological chemokine levels but show delayed recovery when challenged with elevated chemokine concentrations. This work establishes that adaptation to chemokine fluctuations can be “outsourced” from canonical GPCR signaling to an autonomously acting scavenger receptor that both senses and dynamically buffers chemokine levels to increase the robustness of tissue migration. [Display omitted] •Tissue recovers robust migration in the continued presence of a chemokine flood•Chemokine-driven phosphorylation triggers recycling of the scavenger receptor Cxcr7b•Phospho-deficient Cxcr7b mediates migration but not adaption to elevated chemokine levels•Adaptation to chemokine changes outsourced from the guidance receptor Cxcr4 to Cxcr7b Wong et al. address how tissues adapt to changes in guiding chemoattractants in vivo. They show that cell collectives can rapidly resume migration when exposed to acute “chemokine floods”. Experimental investigation of the underlying mechanism reveals that a dedicated scavenger receptor dynamically buffers chemokine levels to ensure robust tissue migration.