Who Stole the Chemokine?

Abstract

Primordial germ cells (PGCs) in the zebrafish embryo face a long migration from the point at which they are specified during development to the location of the future gonad, and it takes some precise signaling to get them there. Major guidance cues are provided by the chemokine SDF-1a (stromal-derived factor-1 alpha), which attracts the PGCs by signaling through its receptor CXCR4b [chemokine (C-X-C motif) receptor 4b]. SDF-1a also binds to another receptor, CXCR7, but the function of this receptor in PGC cell migration has been uncertain. Boldajipour et al. ’s experiments indicate that CXCR7’s function is not to signal but rather to act as a sink that soaks up stray molecules of SDF-1a, thus adding to the precision of SDF-1a signaling through CXCR4b. Transplantation experiments taking PGCs from animals lacking CXCR7 into wild-type embryos showed that the critical function of CXCR7 was in somatic cells, not the PGCs. Microscopy of fluorescently tagged proteins showed that CXCR7 promoted internalization of SDF-1a, and human cells expressing CXCR7 depleted SDF-1a from the culture medium in which they were grown. In vivo, the inhibited motility of PGCs in embryos lacking CXCR7 was reproduced in embryos overexpressing SDF-1a, and depletion of CXCR4b suppressed the CXCR7 phenotype. Analysis of embryos in which SDF-1a was uniformly expressed but CXCR7 was expressed unevenly showed that PGCs moved to domains lacking CXCR7 (where concentrations of SDF-1a were presumably higher). The authors compare this decoy receptor strategy to a similar mechanism that functions in the resolution of inflammatory responses: In that case, interleukin-10 promotes expression of inflammatory chemokine receptors on mature dendritic cells, where they also appear not to signal but instead act to sequester proinflammatory chemokines. B. Boldajipour, H. Mahabaleshwar, E. Kardash, M. Reichman-Fried, H. Blaser, S. Minina, D. Wilson, Q. Xu, E. Raz, Control of chemokine-guided cell migration by ligand sequestration. Cell 132 , 463-473 (2008). [Online Journal]