雌激素受体β调控髓鞘损伤后少突胶质细胞发育的作用机制

(1.厦门大学附属第一医院,福建 厦门 361003; 2.厦门大学生命科学学院,福建 厦门 361102)

雌激素受体β; 少突胶质细胞; miRNA

The mechanistic study on the role of estrogen receptor β in the regulation of oligodendrocyte maturation after myelin injury
HAN Ying 1,OU Zhimin2*

(1.The First Hospital Affiliated to Xiamen University,Xiamen 361003,China; 2.School of Life Sciences,Xiamen University,Xiamen 361102,China)

estrogen receptor β; oligodendrocytes; miRNA

DOI: 10.6043/j.issn.0438-0479.201807027

备注

性别是影响少突胶质细胞(OLs)发育的因素之一,雌激素受体β(ERβ)可能参与了OLs的发育调控,但其作用机制尚未明确.为阐明ERβ如何调控OLs的发育,通过在原代培养的少突胶质细胞前体细胞(OPCs)中过表达相关基因,使用溶血性磷脂酰胆碱(LPC)诱导OLs损伤以及荧光素酶报告基因等方法,考察了OPCs中ERβ如何调节细胞的分化以及ERβ受到哪些因素的调控.结果显示:过表达ERβ基因能够促进OPCs分化; LPC诱导损伤后,少突胶质细胞转录因子-2(Olig2)基因与ERβ的表达水平呈负相关,且过表达Olig2能够抑制OPCs中ERβ的表达水平; 同时,LPC处理可诱导miRNA mmu-miR-219-2的表达,且mmu-miR-219-2能够直接与ERβ基因的3'-非翻译区结合并抑制其表达; 而ERβ则通过与G蛋白偶联受体17(Gpr17)基因的启动子结合抑制Gpr17基因的表达,从而促进OPCs的成熟.综上,Olig2/mmu-miR-219-2/ERβ/Gpr17这一调控通路可能参与了OLs发育过程的调控,有望为临床上脱髓鞘疾病的治疗提供新的靶点.

Gender is one of the factors influencing the development of oligodendrocytes(OLs), and the estrogen receptor β(ERβ)may play a role in this regulation.However,the underlying mechanism remains unclear.To reveal the mechanism about how ERβ regulates the development of OLs,we used several methods including overexpressing some related genes in the primary culture of oligodendrocyte precursor cells(OPCs),inducing injury in OLs by lysolecithin(LPC)treatment and dual-luciferase reporter assays, to investigate the effect ofERβ in regulating OPCs differentiation and the factors that modulate the expression of ERβ.The results showed that overexpression of ERβ gene promoted differentiation of the oligodendrocyte precursor cells.Upon LPC injury,the expression levels of the oligodendrocyte transcription factor-2(Olig2)gene and ERβ were negatively correlated,and overexpression of Olig2 inhibited the level of ERβ in the OPCs.Meanwhile,the expression level of miRNA mmu-miR-219-2 was induced by LPC injury,and mmu-miR-219-2 inhibited the expression level of ERβ through a direct interaction with its 3'-untranslation region.Furthermore,ERβ bound to the promoter region of the G-protein coupled receptor 17(Gpr17)gene and reduced its expression,accelerating the maturation of the OPCs.Taking together,our current study revealed an Olig2/mmu-miR-219-2/ERβ/Gpr17 signaling pathway that participated in the regulation of OLs development,which might potentially provide a novel therapeutic target for the demyelination diseases in clinical practice.