On the other hand, no progenitor

migration was observed in either CXCR7 or CXCR4 mutant mice, indicating that expression of both of these receptors is equally important for directed migration to occur. However, when the authors examined the migratory properties of individual mutant progenitors in cortical slices, they found that CXCR4 mutant cells were more motile and CXCR7 mutant cells were less motile than wild-type cells. Hence the authors conclude that the two receptors must have different, but interdependent, signaling consequences in directing progenitor migration. Further experiments indicated what these signaling pathways might be. It is well known that CXCR4 receptors signal via the pertussis toxin

selleck screening library (PTX)-sensitive G proteins Gαi/o. Using a genetic manipulation for expressing PTX in migrating interneurons, Wang et al. (2011) demonstrated that inhibition of Gαi/o in these cells produces the same phenotype as inhibiting CXCR4, further illustrating the importance of CXCR4 signaling. CXCR7 receptors can’t activate Gαi/o but are able to signal via β-arrestin. As β-arrestin can act as a scaffold protein for intermediates of the MAP kinase pathway, this could represent a signaling option for these receptors. Indeed, Wang et al. (2011) do demonstrate that CXCR7 can activate the MAP kinase Selleckchem Cobimetinib pathway in migrating progenitors. The mechanism of CXCR4/CXCR7 cooperation is beautifully illuminated by the studies of Sánchez-Alcañiz et al. (2011). These authors also conclude that migrating interneurons express both CXCR4 and CXCR7 and that migration is dependent on both receptors. However, they make one further absolutely key observation. They show that migrating cells that lack CXCR7 in CXCR7 mutant mice also lack CXCR4 protein expression (the mRNA is still expressed).Why should CXCR4 disappear if CXCR7 is removed? Sánchez-Alcañiz et al. (2011) show, and Wang et al. (2011) also

observe, that most of the CXCR7 in migrating interneurons is intracellular, something consistent with other papers in the literature. Sánchez-Alcañiz et al. (2011) note that CXCR7 actively recycles between the membrane aminophylline and the interior of the cell. It appears that CXCR7 is constantly involved in binding and internalizing CXCL12. Hence, as they predict, Sánchez-Alcañiz et al. (2011) demonstrate that removal of CXCR7 produces a huge increase in the extracellular levels of CXCL12. Normally, when CXCL12 binds to CXCR4, in addition to G protein activation, it also produces receptor endocytosis and degradation. Hence, if the extracellular CXCL12 concentration is too high, it will trigger endocytosis and degradation of all of the CXCR4 in the cell. Viewed in this way, one can see that the important function for CXCR7 in these cells is to carefully titrate the concentration of CXCL12 in the local microenviroment so that just the right amount of signaling occurs.