The Anti-apoptotic Function And Mechanism Of CXCL12\CXCR4\CXCR7in Neural Progenitor Cells

Chemokines have recently been shown to play important roles in both fetal and adult neurogenesis. Chemokine CXCL12, a CXC chemokine family member, is widely expressed in the central nervous system (CNS) and essential for migration of human neural progenitor cells (hNPCs).CXCR4has been known the unique receptor for CXCL12, however, recently CXCR7has been found the second receptor for CXCL12and more evidence have demonstrated CXCL12can although function through CXCR7. Now little is known about the function of CXCR7in hNPCs. Our studies are mainly focus on the function and mechanism of CXCL12\CXCR4\CXCR7system in neural progenitor cells.First, using a primary hNPCs culture system, we demonstrated that CXCL12promotes hNPCs survival in the events of camptothecin-induced apoptosis and that this effect requires both CXCR7and CXCR4. Through FACS analysis and immunocytochemistry, we determined that CXCR7is mainly localized in the early endosome, while CXCR4is more broadly expressed at the cell surface and on both early and recycling endosomes. Furthermore, we found that endocytosis is required for the pro-survival function of CXCL12.Using dual-color total internal reflection fluorescence microscopy (TIRFm) we demonstrated that CXCR7quickly trafficks to plasma membrane in mediating CXCL12endocytosis and using confocal microscope and immunoprecipitation, we further confirmed the increased interaction between CXCR7and CXCR4after CXCL12treatment. Investigating the molecular mechanisms by which the CXCL12-induced endocytosis promotes cell survival also revealed a critical role for sustained ERK1/2activation. CXCL12quickly induces ERK1/2activation through CXCR4-mediated GPCR signaling and also induces sustained ERK1/2activation through CXCR7-and CXCR4-mediated endocytotic signaling pathway. Consistent with these findings, significant higher number of apoptotic NPCs were found in the developing brain of CXCR7knockout mice using TUNEL method.In conclusion, CXCL12protects hNPCs from apoptotic challenges through CXCR7-and CXCR4-mediated endocytotic signaling. Since survival of hNPCs is important for neurogenesis, CXCR7may become a new therapeutic target to properly regulate the critical processes of brain development.