CXCR7 prevents excessive CXCL12-mediated downregulation of CXCR4 in migrating cortical interneurons

Abstract

The CXCL12/CXCR4 signaling pathway is involved in the development of numerous neuronal and non-neuronal structures. Recent work established that the atypical second CXCL12 receptor, CXCR7, is essential for the proper migration of interneuron precursors in the developing cerebral cortex. Two CXCR7-mediated functions were proposed in this process: direct modulation of β-arrestin-mediated signaling cascades and CXCL12 scavenging to regulate local chemokine availability and ensure responsiveness of the CXCL12/ CXCR4 pathway in interneurons. Neither of these functions has been proven in the embryonic brain. Here, we demonstrate that migrating interneurons efficiently sequester CXCL12 through CXCR7. CXCR7 ablation causes excessive phosphorylation and downregulation of CXCR4 throughout the cortex in mice expressing CXCL12, but not in CXCL12-deficient animals. Cxcl12 −/− mice lack activated CXCR4 in embryonic brain lysates and display a similar interneuron positioning defect as Cxcr4−/− and Cxcl12 −/−;Cxcr7 −/− animals. Thus, CXCL12 is the only CXCR4-activating ligand in the embryonic brain and deletion of one of the CXCL12 receptors is sufficient to generate a migration phenotype that corresponds to the CXCL12-deficient pathway. Our findings imply that interfering with the CXCL12-scavenging activity of CXCR7 causes loss of CXCR4 function as a consequence of excessive CXCL12-mediated CXCR4 activation and degradation.

Intermediate Progenitors Facilitate Intracortical Progression of Thalamocortical Axons and Interneurons through CXCL12 Chemokine Signaling

“…Several findings suggest that the chemokine CXCL12 (stromal cell-derived factor-1) via its receptors CXCR4 and CXCR7 acts as such a coordinating signal. First, in addition to the meninges, CXCL12 is highly expressed in IPCs and guides migrating interneurons in the cortex (Stumm et al, 2003;Tiveron et al, 2006;Stumm and Hollt, 2007;Li et al, 2008;Lysko et al, 2011;Wang et al, 2011;Abe et al, 2014). Second, we observed that CXCR4 is highly expressed in the forming thalamus and TCAs.…”

“…6F ). Quantification of interneuron distribution in the cortex has been described (Abe et al, 2014). Axon outgrowth from thalamus explants was quantified by measuring the 20 longest axons in each explant with ImageJ using the NeuronJ plug-in (illustrated in Fig.…”

“…Cxcl12 mRNA is expressed in the meninges, in the SVZ, and to lesser extent, in the subplate (Stumm et al, 2003(Stumm et al, , 2007Abe et al, 2014). The chemokine is attractant for interneurons and supports tangential migration in the cortex.…”

“…The chemokine is attractant for interneurons and supports tangential migration in the cortex. Both CXCL12 receptors, CXCR4 and CXCR7, are involved in this process Wang et al, 2011;Abe et al, 2014). The prominent Cxcl12 mRNA signal in the SVZ is localized in IPC (Tiveron et al, 2006).…”

Chemokine Signaling Controls Integrity of Radial Glial Scaffold in Developing Spinal Cord and Consequential Proper Position of Boundary Cap Cells

“…It may act as a signaling receptor either independently or cooperatively with CXCR4. It is also possible that CXCR7 serves as a scavenger receptor to sequester CXCL12 to prevent excessive CXCL12-mediated CXCR4 downregulation via endocytosis, similar to what has been demonstrated for CXCR7 in the migration of the cortical interneurons (Abe et al, 2014).…”