Cxcr7 expression waned between E15.5 and E18.5 (

Figure 1 and Figure S1). This interval correlates with the period when a large flux of interneurons invade the cortical plate ( Lopez-Bendito et al., 2008). Perhaps downregulation of Cxcr7 results Regorafenib in reduced interneuron responsiveness to CXCL12, thereby enabling their entry into the cortical plate. This is consistent with our electroporation experiments showing that interneurons require both CXCR4 and CXCR7 receptors to respond to CXCL12-mediated chemoattraction. Several lines of evidence suggest that both CXCR4 and CXCR7 regulate CXCL12 signaling in migrating interneurons. Cxcr4−/− and Cxcr7−/− mutants had nearly equivalent interneuron positioning phenotypes. In addition, both Cxcr4 and Cxcr7 were required for attraction to ectopic CXCL12. Thirdly, the CXCR4 blockage did not exacerbate the Panobinostat solubility dmso phenotype observed in the Cxcr7−/− mutants. These experiments provide evidence that signaling through both CXCR4 and CXCR7 are essential in guiding migrating interneurons. After entering the cortical plate, movements of Lhx6-GFP+ cells from the Cxcr4−/− and Cxcr7−/− mutants exhibited opposite phenotypes: CXCR4-deficient neurons were highly motile and elaborated a longer leading process, whereas CXCR7-deficient neurons were

much less motile and had a shorter leading process. These results suggest that signaling downstream of CXCR4 and CXCR7 have distinct effects on cytoskeletal organization as previous studies have shown that actin and microtubule dynamics are the main cytoskeletal contribution responsible for cell motility ( Baudoin et al., 2008, Etienne-Manneville, 2004 and Reiner and Sapir, 2009). Our result also implies that both receptors are required for the interneurons to coordinate their movements in response to guidance cues in the cortex and eventually situate themselves in their appropriate cortical positions. Indeed, there are interneuron lamination defects in the adult

cortex of interneuron-specific Cxcr4 and Cxcr7 conditional mutants ( Figure S7; Li et al. 2008). Our data demonstrated that blocking TCL Gα(i/o) signaling in vivo, using PTX, phenocopied the CXCR4 mutant (Figure 8B and Figure S8B), consistent with CXCR4′s known ability to signal through Gα(i/o) (Albert and Robillard, 2002, Hamm, 1998, Hesselgesser et al., 1998, Ma et al., 1998, Patrussi and Baldari, 2008 and Teicher and Fricker, 2010). On the other hand, because CXCR7 does not appear to signal through heteromeric G proteins, the mechanism underlying its function has been controversial. CXCR7 has been reported to regulate responses to CXCL12 in tissue culture cells, where CXCR4 and CXCR7 form heterodimers (Levoye et al., 2009 and Sierro et al., 2007).