Positional information is crucial during development and often relies upon the distribution of molecules along a gradient. Different concentrations of these molecules may trigger specific developmental programmes or function as a guide for migrating cells to find their target destinations. Erez Raz and colleagues report in Cell that the zebrafish receptor CXCR7 sequesters the chemokine SDF-1a, allowing the rapid changes in its distribution that are required for primordial germ cell (PGC) migration.

SDF-1a is internalized by CXCR7-expressing cells. Somatic cells (red membrane labelling) expressing CXCR7 (right panel) show uptake of SDF-1a-EGFP (green) unlike control cells expressing CXCR4b (left panel).

Image courtesy of Dr. Erez Raz, Center of Molecular Biology of Inflammation, Münster, Germany.

SDF-1a has two receptors - CXCR4b and CXCR7 - but whereas the role for CXCR4b in guided cell migration is well characterised, the function of CXCR7 in vivo remains controversial. By knocking down CXCR7 in zebrafish embryos, Erez Raz and colleagues show that this receptor is required for correct PGC migration.

Surprisingly, during early development cxcr7 was expressed throughout the embryo; however, unlike crcx4b, it was not detected in migrating PGCs, suggesting the receptor may function in the somatic environment. This was confirmed by the observation that PGCs lacking CXCR7 efficiently reached their target when transplanted into wild-type embryos, whereas normal cells transplanted into CXCR7-depleted embryos failed to migrate.

The path followed by migrating PGCs tightly correlates with changes in sdf-1a mRNA expression. Importantly, CXCR7 did not affect sdf-1a transcript distribution, but fluorescently-tagged CXCR7 did co-localize with SDF-1a in intracellular structures. This, together with the observations that CXCR7 morphants have higher levels of extracellular SDF-1a, and exposure to CXCR7-expressing somatic cells promoted SDF-1a internalization, shows CXCR7 sequesters SDF-1a and affects its gradient. CXCR7 knockdown had no effect on signalling pathways downstream of the chemokine receptors, suggesting the receptor is silent.

PGCs in CXCR7-depleted embryos exhibited reduced polarization and had strongly reduced motility, manifested by short migration tracks. The hypothesis that the CXCR7 loss-of-function phenotype results from higher levels of extracellular SDF-1a was confirmed by global SDF-1a expression, which led to a similar phenotype. Furthermore, simultaneous knockdown of both CXCR7 and SDF-1a, or CXCR7 and CXCR4b, reversed this phenotype. PGCs mimicked behaviour seen in absence of guidance cues - cells regained motility but were dispersed throughout the embryo.

Finally, Erez Raz and colleagues confirmed that somatically expressed CXCR7 affects migration of PGCs in vivo; if an uneven distribution of the receptor was superimposed on uniformly expressed SDF-1a, PGCs accumulated at regions lacking CXCR7.

Together, this work shows that the CXCR7 receptor is required for the correct migration of PGCs in zebrafish embryos, and that it functions by clearing SDF-1a. CXCR7 may also shape the SDF-1a gradient and reduce the time it is available, thus allowing the dynamic changes required for guiding migrating PGCs. Whether CXCR7 functions similarly in other tissues remains to be determined.

Author: Kim Baumann