Conditional Deletion of Foxg1 Alleviates Demyelination and Facilitates Remyelination via the Wnt Signaling Pathway in Cuprizone-Induced Demyelinated Mice

Abstract

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conditional knockout and wild-type (WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination.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.

Multidimensional Functional Profiling of Human Neuropathogenic FOXG1 Alleles in Primary Cultures of Murine Pallial Precursors

“…Unexpectedly, both alleles quantitatively phenocopied their healthy counterpart, suggesting that the corresponding mutations may not differentially perturb the oligodendrogliogenic bias of pallial NSCs (Figures 8A,B and S4 (top)). It was also previously reported that Foxg1 promotes proliferation of oligodendroglial progenitors, delaying their terminal differentiation [32]. Again, we verified that this also applies to human FOXG1.…”

“…Notwithstanding that, we are confident that Foxg1 biological activities detected by our experimental platform are genuine, as they nicely mirror the results of a number of loss-of-function studies performed on the same gene by other Teams and ours. This applies to investigation of NSC fate choice [5,6], proliferation of neuronogenic [4] and oligodendrogenic [32] progenitors, dendritic architecture [11] and neuronal activity [14].…”

Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation

“…Very interestingly, this seems to be a mechanism that can also regulate Fzd1 expression levels, among other Wnt target genes. Mechanisms such as activation of PPARg and downregulation of Foxg1 can also potentially intersect with and inhibit the Wnt pathway (Vallé e et al, 2018;Dong et al, 2021) through activation of GSK-3b inducing proteasomal b-catenin degradation, and PPARg agonists could serve as promising treatments during demyelinating injury (Vallé e et al, 2018). Our results indicate that Rnf43 is a potent regulator of the timing of remyelination, an important determinant of functional recovery in human MS and animal models.…”

Unilateral facial injection of Botulinum neurotoxin A attenuates bilateral trigeminal neuropathic pain and anxiety-like behaviors through inhibition of TLR2-mediated neuroinflammation in mice

“…Low doses of BoNT/A were not adequate to produce muscle dysfunction, instead, sensory-motor recovery was accelerated by stimulating the regeneration of axon myelination [ 44 ]. However, whether injection of BoNT/A promotes myelin regeneration or not warrants further investigation [ 45 ].…”