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 Foxg1 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 Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone (CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type (WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination.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, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated 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 Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3β, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.

各种病理因素引起的少突胶质细胞大量丢失是许多中枢神经系统脱髓鞘疾病的基本特征。基于各种研究，现在已经确定，少突胶质前体细胞 (OPCs) 对轴突分化和髓鞘再生的损害是脱髓鞘疾病治疗失败的重要事件。最近的证据表明，Foxg1对于某些前体的增殖和抑制大脑发育过程中的过早神经发生至关重要。迄今为止，很少有人关注Foxg1在中枢神经系统脱髓鞘疾病中OPCs增殖和分化中的作用。在这里，我们第一次检查了Foxg1的影响使用铜宗 (CPZ) 诱导的小鼠模型研究大脑中的脱髓鞘和髓鞘再生。在这项工作中，7 周大的Foxg1条件性敲除和野生型 (WT) 小鼠被喂食含有 0.2% CPZ w/w 的饮食 5 周，之后撤出 CPZ 以实现髓鞘再生。我们的研究结果表明，与 WT 小鼠相比，Foxg1基因敲除小鼠不仅表现出脱髓鞘减轻，而且脱髓鞘胼胝体的髓鞘再生加速。此外，我们发现Foxg1敲除降低了 OPCs 的增殖并加速了它们在体内和体外向成熟少突胶质细胞的分化。. Wnt 信号传导在发育和多种疾病中起关键作用。GSK-3β 是 Wnt 通路中的一种关键调节激酶，可调节 β-catenin 进入细胞核的能力，从而激活 Wnt 靶基因的表达。然后，我们使用 GSK-3β 活性的选择性抑制剂 SB216763 来进一步证明Foxg1在体外影响 OPCs的调节机制。结果表明，SB216763明显抑制GSK-3β的表达，从而消除了敲低Foxg1引起的OPCs增殖和分化的影响。这些结果表明Foxg1通过 Wnt 信号通路参与 OPCs 的增殖和分化。目前的实验结果首次表明Foxg1是治疗中枢神经系统脱髓鞘疾病的新治疗靶点。