SDF1α/CXCR4 signaling stimulates β-catenin transcriptional activity in rat neural progenitors

Stromal cell-derived factor (SDF-1), by activating its cognate receptor CXCR4, plays multiple roles in cell migration, proliferation and survival in the development of the central nervous system. Recently, we have shown that functional SDF1α/CXCR4 signaling mediates chemotaxis through extracellular signal-regulated kinase (ERK) activation in the developing spinal cord. Here, we report that SDF1α/CXCR4 signaling activates β-catenin/TCF transcriptional activity in embryonic rat spinal cord neural progenitors. Stimulation of neural progenitors with SDF1α resulted in cytoplasmic β-catenin accumulation in 30 min, and lasted for approximately 240 min, while Wnt3a, a positive control, stabilized cytoplasmic β-catenin in 120 min. Dose-response studies indicated that the β-catenin stabilization effect could be detected in cells exposed to fM concentrations of SDF1α. This SDF1α-induced β-catenin stabilization effect was inhibited by pretreatment of the cells with either pertussis toxin (PTX), an inactivator of G protein-coupled receptors, or PD98059, a MEK1 inhibitor. Concomitant with β-catenin accumulation in the cytoplasm, SDF1α enhanced nuclear translocation of β-catenin and its binding to nuclear transcription factor T cell-specific transcription factor/lymphoid enhancer-binding factor (TCF/LEF). Furthermore, SDF1α increased expression of genes such as Ccnd1, 2, 3, and c-Myc known as targets of the Wnt/β-catenin/TCF pathway. The increased expression of Ccnd1 and c-Myc by SDF1α was further confirmed by immunoblot analysis. Our data suggest that SDF1α/CXCR4 signaling may interact with the Wnt/β-catenin/TCF pathway to regulate the development of the central nervous system.