SDF1alpha/CXCR4 signaling stimulates beta-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 SDF1alpha/CXCR4 signaling mediates chemotaxis through extracellular signal-regulated kinase (ERK) activation in the developing spinal cord. Here, we report that SDF1alpha/CXCR4 signaling activates beta-catenin/TCF transcriptional activity in embryonic rat spinal cord neural progenitors. Stimulation of neural progenitors with SDF1alpha resulted in cytoplasmic beta-catenin accumulation in 30 min, and lasted for approximately 240 min, while Wnt3a, a positive control, stabilized cytoplasmic beta-catenin in 120 min. Dose-response studies indicated that the beta-catenin stabilization effect could be detected in cells exposed to fM concentrations of SDF1alpha. This SDF1alpha-induced beta-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 beta-catenin accumulation in the cytoplasm, SDF1alpha enhanced nuclear translocation of beta-catenin and its binding to nuclear transcription factor T cell-specific transcription factor/lymphoid enhancer-binding factor (TCF/LEF). Furthermore, SDF1alpha increased expression of genes such as Ccnd1, 2, 3, and c-Myc known as targets of the Wnt/beta-catenin/TCF pathway. The increased expression of Ccnd1 and c-Myc by SDF1alpha was further confirmed by immunoblot analysis. Our data suggest that SDF1alpha/CXCR4 signaling may interact with the Wnt/beta-catenin/TCF pathway to regulate the development of the central nervous system.
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
Yongquan
Y
Luo
Jingli
J
Cai
Haipeng
H
Xue
Mark P
MP
Mattson
Mahendra S
MS
Rao
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013116:Spinal Cord / Q000166:cytology; D013234:Stem Cells / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000502:physiology; D060508:Wnt3 Protein; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology*
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin