Migration of oligodendrocyte precursors along axons is a necessary prerequisite for myelination, but little is known about underlying mechanisms. NG2 is a large membrane proteoglycan implicated in oligodendrocyte migration. Here we show that a PDZ domain protein, termed syntenin-1, interacts with NG2 and that syntenin-1 is necessary for normal rates of migration. The association of syntenin-1 with NG2, identified in a yeast-2-hybrid screen, was confirmed by co-localization of both proteins within processes of oligodendroglial precursor cells and by co-immunoprecipitation from cell extracts. Syntenin-1 also colocalizes with NG2 in 'co-capping' assays, demonstrating a lateral association of both proteins in live oligodendrocytes. RNAi-mediated downregulation of syntenin-1 in glial cells results in a significant reduction of migration in vitro, as does the presence of polyclonal antibody against NG2. Thus Syntenin plays a role in the migration of oligodendroglial precursors, and we suggest that NG2-syntenin-1 interactions contribute to this.