GSK3β promotes the differentiation of oligodendrocyte precursor cells via β-catenin-mediated transcriptional regulation.

Oligodendrocytes are generated by the differentiation and maturation of oligodendrocyte precursor cells (OPCs). The failure of OPC differentiation is a major cause of demyelinating diseases; thus, identifying the molecular mechanisms that affect OPC differentiation is critical for understanding the myelination process and repairing after demyelination. Although prevailing evidence shows that OPC differentiation is a highly coordinated process controlled by multiple extrinsic and intrinsic factors, such as growth factors, axon signals, and transcription factors, the intracellular signaling in OPC differentiation is still unclear. Here, we showed that glycogen synthase kinase 3β (GSK3β) is an essential positive modulator of OPC differentiation. Both pharmacologic inhibition and knockdown of GSK3β remarkably suppressed OPC differentiation. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assays and Ki67 staining showed that the effect of GSK3β on OPC differentiation was not via cell death. Conversely, activated GSK3β was sufficient to promote OPC differentiation. Our results also demonstrated that the transcription of myelin genes was regulated by GSK3β inhibition, accompanying accumulated nuclear β-catenin, and reduced the expression of transcriptional factors that are relevant to the expression of myelin genes. Taken together, our study identified GSK3β as a profound positive regulator of OPC differentiation, suggesting that GSK3β may contribute to the inefficient regeneration of oligodendrocytes and myelin repair after demyelination.