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

Nat Cell Biol. 2020 Mar;22(3):266-273. doi: 10.1038/s41556-020-0465-4. Epub 2020 Feb 10.

Abstract

Chemoattractant gradients frequently guide migrating cells. To achieve the most directional signal, such gradients should be maintained with concentrations around the dissociation constant (Kd)1-6 of the chemoreceptor. Whether this actually occurs in animals is unknown. Here we investigate whether a moving tissue, the zebrafish posterior lateral line primordium, buffers its attractant in this concentration range to achieve robust migration. We find that the Cxcl12 (also known as Sdf1) attractant gradient ranges from 0 to 12 nM, values similar to the 3.4 nM Kd of its receptor Cxcr4. When we increase the Kd of Cxcl12 for Cxcr4, primordium migration is less directional. Furthermore, a negative-feedback loop between Cxcl12 and its clearance receptor Ackr3 (also known as Cxcr7) regulates the Cxcl12 concentrations. Breaking this negative feedback by blocking the phosphorylation of the cytoplasmic tail of Ackr3 also results in less directional primordium migration. Thus, directed migration of the primordium is dependent on a close match between the Cxcl12 concentration and the Kd of Cxcl12 for Cxcr4, which is maintained by buffering of the chemokine levels. Quantitative modelling confirms the plausibility of this mechanism. We anticipate that buffering of attractant concentration is a general mechanism for ensuring robust cell migration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Line
  • Cell Movement*
  • Chemokine CXCL12 / metabolism
  • Chemokines / metabolism*
  • Feedback, Physiological
  • Humans
  • Receptors, CXCR / metabolism
  • Receptors, CXCR4 / metabolism
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish / metabolism
  • Zebrafish Proteins / metabolism

Substances

  • CXCR4 protein, human
  • CXCR4b protein, zebrafish
  • CXCR7 protein, zebrafish
  • Chemokine CXCL12
  • Chemokines
  • Receptors, CXCR
  • Receptors, CXCR4
  • Zebrafish Proteins
  • cxcl12a protein, zebrafish