G protein-coupled receptor 17 is regulated by WNT pathway during oligodendrocyte precursor cell differentiation

Abstract

G protein-coupled receptor 17 (GPR17) and the WNT pathway are critical players of oligodendrocyte (OL) differentiation acting as essential timers in developing brain to achieve fully-myelinating cells. However, whether and how these two systems are related to each under is still unknown. Of interest, both factors are dysregulated in developing and adult brain diseases, including demyelination disorders and cancer, making the understanding of their reciprocal interactions of potential importance for identifying new targets and strategies for myelin repair. Here, we examined regulatory mechanisms linking WNT signalling to GPR17 expression in OLs. We analyzed the relative expressions of mRNAs encoding GPR17 and the T cell factor/Lymphoid enhancer-binding factor-1 (TCF/LEF) transcription factors of the canonical WNT/b-CATENIN pathway in both PDGFRa+ and O4+ OLs during mouse post-natal development. In O4+ cells, Gpr17mRNA level peaked at post-natal day 14 and then decreased concomitantly to the physiological uprise of WNT tone, as shown by increasedLef1 mRNA level. The link between WNT signaling and GPR17 expression was further reinforced in vitro in primary PDGFRa+ cells and in the Oli-neu cell line. High WNT tone impaired OL differentiation and drastically reduced GPR17 mRNA and protein levels. In Oli-neu cells, we demonstrated that WNT/b-CATENIN activation represses Gpr17 promoter activity through both putative WNT response elements (WRE) and upregulation of the inhibitor of DNA-binding protein 2 (Id2). We conclude that WNT pathway influences oligodendrocyte maturation by repressing GPR17 which could have implications in pathologies characterized by dysregulations of the oligodendroglial lineage including multiple sclerosis and oligodendroglioma.