Conditional Deletion Offoxg1alleviates Demyelination And Facilitates Remyelinationviathe Wnt Signaling Pathway In Cuprizone-Induced Demyelinated Mice

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 thatFoxg1is 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 ofFoxg1in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects ofFoxg1on demyelination and remyelination in the brain using a cuprizone (CPZ)-induced mouse model. In this work, 7-week-oldFoxg1conditional knockout and wild-type (WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination.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,Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found thatFoxg1knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes bothin vivoandin vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3 beta, a key regulatory kinase in the Wnt pathway, regulates the ability of beta-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763, a selective inhibitor of GSK-3 beta activity, to further demonstrate the regulatory mechanism by whichFoxg1affects OPCsin vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3 beta, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown ofFoxg1. These results suggest thatFoxg1is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest thatFoxg1is a new therapeutic target for the treatment of demyelinating diseases of the CNS.