Conditional Deletion of Foxgl Alleviates Demyelination and Facilitates Remyelination via the Wnt Signaling Pathway in Cuprizone-Induced Demyelinated Mice

• 来源期刊: 神经科学通报（英文版）
• 年，卷（期）: 2021,（1）
• 所属期刊栏目: Original Articles
• 页码范围: 15-30
• 页数: 16页
• 语种: 英文

摘要

The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS).Based on a variety of studies,it is now well established that impairment of oligodendrocyte precursor cells(OPCs)to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases.Recent evidence suggests that Foxgl is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development.To date,very little attention has been paid to the role of Foxgl in the proliferation and differentiation of OPCs in demyeli-nating diseases of the CNS.Here,for the first time,we examined the effects of Foxgl on demyelination and remyelination in the brain using a cuprizone(CPZ)-induced mouse model.In this work,7-week-old Foxgl conditional knockout and wild-type(WT)mice were fed a diet containing 0.2％CPZ w/w for 5 weeks,after which CPZ was withdrawn to enable remyelination.Our results demonstrated that,compared with WT mice,Foxgl-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum.Furthermore,we found that Foxgl knockout decreased the proliferation of OPCs and accel-erated their differentiation into mature oligodendrocytes both in vivo and in vitro.Wnt signaling plays a critical role in development and in a variety of diseases.GSK-3β,a key regulatory kinase in the Wnt pathway,regulates the ability of β-catenin to enter nuclei,where it activates the expression of Wnt target genes.We then used SB216763,a selective inhibitor of GSK-3β activity,to further demonstrate the regulatory mechanism by which Foxgl affects OPCs in vitro.The results showed that SB216763 clearly inhibited the expression of GSK-3β,which abol-ished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxgl.These results suggest that Foxgl is involved in the proliferation and differentiation of OPCs through the Wnt signaling path-way.The present experimental results are some of the first to suggest that Foxgl is a new therapeutic target for the treatment of demyelinating diseases of the CNS.