A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration.

Abstract

Chemoattractant gradients often guide migrating cells. To achieve the greatest directional signal over noise, such gradients should be maintained with concentrations around the chemoreceptor’s dissociation constant (Kd) 1–6. Whether this is true in animals is unknown. Here, we investigate whether a moving tissue, the zebrafish posterior lateral line primordium, buffers its attractant in this concentration range for robust migration. We find that the Cxcl12/Sdf1 attractant gradient ranges from 0 to 12 nM and thus borders around the 3.4 nM Kd of its receptor Cxcr4. When we increase the Cxcl12-Cxcr4 Kd, primordium migration is less directional. Furthermore, a negative feedback loop between Cxcl12 and its clearance receptor Ackr3/Cxcr7 regulates the Cxcl12 concentrations. Breaking this negative feedback by blocking the phosphorylation of Ackr3b’s cytoplasmic tail also results in less directional primordium migration. Thus, the primordium relies on a close match between the Cxcl12 concentration and the Cxcl12-Cxcr4 Kd for directed migration which it maintains by buffering the chemokine levels. Quantitative modeling confirms the plausibility of this mechanism. We anticipate that attractant concentration buffering is a general mechanism to ensure robust cell migration.