A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration. Nat Cell Biol 2020 Mar;22(3):266-273
Date
02/12/2020Pubmed ID
32042179Pubmed Central ID
PMC7809593DOI
10.1038/s41556-020-0465-4Scopus ID
2-s2.0-85079456516 (requires institutional sign-in at Scopus site) 38 CitationsAbstract
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.
Author List
Lau S, Feitzinger A, Venkiteswaran G, Wang J, Lewellis SW, Koplinski CA, Peterson FC, Volkman BF, Meier-Schellersheim M, Knaut HAuthors
Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of WisconsinBrian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Genetically Modified
Cell Line
Cell Movement
Chemokine CXCL12
Chemokines
Feedback, Physiological
Humans
Receptors, CXCR
Receptors, CXCR4
Zebrafish
Zebrafish Proteins
