G 蛋白偶联受体 17 (GPR17) 和 WNT 通路是少突胶质细胞 (OL) 分化的关键参与者，在大脑发育过程中充当重要的定时器，以实现全髓鞘细胞的形成。然而，这两个系统是否以及如何相互关联仍然未知。有趣的是，这两个因素在发育中和成人脑部疾病（包括白质损伤和癌症）中都失调，因此了解它们的相互作用对于确定髓磷脂修复的新靶点和策略具有潜在的重要性。在这里，通过药理学和生物技术相结合的方法，我们研究了将 WNT 信号传导与 OL 中 GPR17 表达联系起来的调控机制。我们首先分析了小鼠术后PDGFRα和O4 OL中编码GPR17和经典WNT/β-CATENIN途径的T细胞因子/淋巴增强子结合因子-1 (TCF/LEF)转录因子的mRNA的相对表达。出生发育。在 O4 细胞中，Gpr17 mRNA 水平在出生后第 14 天达到峰值，然后随着 WNT 音调的生理上升而下降，如 Lef1 mRNA 水平增加所示。 WNT 信号传导与 GPR17 表达之间的联系在体外在原代 PDGFRα 细胞和 Oli-neu 细胞中得到进一步加强。高 WNT 音调损害 OL 分化并显着降低 GPR17 mRNA 和蛋白质水平。在 Oli-neu 细胞中，WNT/β-CATENIN 激活通过推定的 WNT 反应元件 (WRE) 和 DNA 结合蛋白 2 (Id2) 抑制剂的上调抑制 Gpr17 启动子活性。我们的结论是，WNT 通路通过抑制 GPR17 影响 OL 成熟，这可能对以 OL 谱系失调为特征的病理学产生影响，包括多发性硬化症和少突胶质细胞瘤。版权所有 © 2023。由 Elsevier Inc. 出版。

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 other is still unknown. Of interest, both factors are dysregulated in developing and adult brain diseases, including white matter injury and cancer, making the understanding of their reciprocal interactions of potential importance for identifying new targets and strategies for myelin repair. Here, by a combined pharmacological and biotechnological approach, we examined regulatory mechanisms linking WNT signaling to GPR17 expression in OLs. We first analyzed the relative expression of mRNAs encoding for GPR17 and the T cell factor/Lymphoid enhancer-binding factor-1 (TCF/LEF) transcription factors of the canonical WNT/β-CATENIN pathway, in PDGFRα+ and O4+ OLs during mouse post-natal development. In O4+ cells, Gpr17 mRNA level peaked at post-natal day 14 and then decreased concomitantly to the physiological uprise of WNT tone, as shown by increased Lef1 mRNA level. The link between WNT signaling and GPR17 expression was further reinforced in vitro in primary PDGFRα+ cells and in Oli-neu cells. High WNT tone impaired OL differentiation and drastically reduced GPR17 mRNA and protein levels. In Oli-neu cells, WNT/β-CATENIN activation repressed Gpr17 promoter activity through both putative WNT response elements (WRE) and upregulation of the inhibitor of DNA-binding protein 2 (Id2). We conclude that the WNT pathway influences OL maturation by repressing GPR17, which could have implications in pathologies characterized by dysregulations of the OL lineage including multiple sclerosis and oligodendroglioma.Copyright © 2023. Published by Elsevier Inc.