Cxcr7 Controls Neuronal Migration by Regulating Chemokine Responsiveness

Abstract

The chemokine Cxcl12 binds Cxcr4 and Cxcr7 receptors to control cell migration in multiple biological contexts, including brain development, leukocyte trafficking, and tumorigenesis. Both receptors are expressed in the CNS, but how they cooperate during migration has not been elucidated. Here, we used the migration of cortical interneurons as a model to study this process. We found that Cxcr4 and Cxcr7 are coexpressed in migrating interneurons, and that Cxcr7 is essential for chemokine signaling. Intriguingly, this process does not exclusively involve Cxcr7, but most critically the modulation of Cxcr4 function. Thus, Cxcr7 is necessary to regulate Cxcr4 protein levels, thereby adapting chemokine responsiveness in migrating cells. This demonstrates that a chemokine receptor modulates the function of another chemokine receptor by controlling the amount of protein that is made available for signaling at the cell surface.

Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome

“…S1). These changes are reminiscent of those reported for a small number of single-gene mutations that disrupt interneuron migration and placement, including Cxcr4 (22), Lhx6 (26), and Cxcr7 (27).…”

“…Our previous work indicates that interneuron distribution is altered in the LgDel cortex, with an apparent shift of parvalbumin cells toward more superficial layers at the expense of deeper layers (18). To determine whether this defect is similar to those associated with other mutations that alter laminar distribution of interneurons (22,26,27), we evaluated the frequency and laminar distribution of molecularly distinct interneuron classes in the LgDel mouse. Among four subtypes, we found specific disruption of parvalbumin interneurons ( Fig.…”

“…Changes in the distribution of cortical interneurons have been associated with genetic mutations that disrupt the migration of these cells during early development (22,26,27). To determine whether migration of basal forebrain-derived interneurons into the cortical rudiment is indeed altered in the LgDel 22q11.2DS model, we used a Dlx5/6 Cre-IRES-eGFP (CIE) reporter mouse line that labels postmitotic neurons generated in the basal forebrain (29).…”

β-arrestin control of late endosomal sorting facilitates decoy receptor function and chemokine gradient formation

“…Cxcr7 function is important for heart development (Sierro et al, 2007), interneuron migration (Sánchez-Alcañiz et al, 2011;Wang et al, 2011), leukocyte trafficking (Cruz-Orengo et al, 2011) and for promoting breast and lung tumorigenesis (Miao et al, 2007;Luker et al, 2012). Some of these in vivo studies, as well as those conducted in vitro (Luker et al, 2010;Naumann et al, 2010), are consistent with the idea that Cxcr7 serves as a receptor that effectively scavenges Cxcl12a and does not influence downstream signaling pathways (reviewed by Mantovani et al, 2006).…”

Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex

“…On the other hand, the expression of a second receptor of CXCL12 (CXCR7) has been reported in CR cells 59 . Thus, we cannot rule out that Sema3E/ PlexinD1 may also act on CXCR7 functions on CXCR4-mediated chemoattraction in CR cells as indicated 59 similarly as happens in subventricular cells in the rostral migratory stream 59 or cortical interneurons 60 . In fact, current experiments of our laboratory are exploring this challenging hypothesis.…”