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 establish...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conditional knockout and wild-type(WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination.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-3 b, a key regulatory kinase in the Wnt pathway, regulates the ability of b-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763,a selective inhibitor of GSK-3 b 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-3 b, 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.展开更多
Objective： Recent evidence indicates that the increased expression of FOXG1 is associated with tumor genesis. This study was designed to explore the expression and role which FOXG1 plays in human glioma. Methods： We...Objective： Recent evidence indicates that the increased expression of FOXG1 is associated with tumor genesis. This study was designed to explore the expression and role which FOXG1 plays in human glioma. Methods： We detected the expression of FOXG1 by immunohistochemistry in glioma tissue samples. Following the down-regulation of FOXG1 in glioma cell lines by a specific short hairpin RNA, the function of FOXG1 in proliferation and apoptosis was assessed. Results： Glioma tissues exhibited notably higher expression of FOXG1 compared with control brain tissues and was positively corre- lated with histological malignancy. The down-regulation of FOXG1 in glioma cells led to a cell apoptosis in vitro. Cenclusion： The overexpression of FOXG1 is a novel glioma malignancy marker, and FOXG1 may be used as a new target in therapeutic strategies for human glioma.展开更多
The Wnt signaling pathway plays key roles in various developmental processes.Wnt5a,which activates the non-canonical pathway,has been shown to be particularly important for axon guidance and outgrowth as well as dendr...The Wnt signaling pathway plays key roles in various developmental processes.Wnt5a,which activates the non-canonical pathway,has been shown to be particularly important for axon guidance and outgrowth as well as dendrite morphogenesis.However,the mechanism underlying the regulation of Wnt5a remains unclear.Here,through conditional disruption of Foxg1 in hippocampal progenitors and postmitotic neurons achieved by crossing Foxg1~(fl/fl)with Emx1-Cre and Nex-Cre,respectively,we found that Wnt5a rather than Wnt3a/Wnt2b was markedly upregulated.Overexpression of Foxg1 had the opposite effects along with decreased dendritic complexity and reduced mossy fibers in the hippocampus.We further demonstrated that FOXG1 directly repressed Wnt5a by binding to its promoter and one enhancer site.These results expand our knowledge of the interaction between Foxg1 and Wnt signaling and help elucidate the mechanisms underlying hippocampal development.展开更多
基金supported by the National Natural Science Foundation of China(81771337 and 81271345)the National Key R&D Program of China(2017YFA0104202)+2 种基金the Natural Science Foundation of Jiangsu Province(BK20161174)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(18KJB180028)the Six Talent Peaks Project in Jiangsu Province(2015 to RY)。
文摘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-3 b, a key regulatory kinase in the Wnt pathway, regulates the ability of b-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763,a selective inhibitor of GSK-3 b 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-3 b, 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.
文摘Objective： Recent evidence indicates that the increased expression of FOXG1 is associated with tumor genesis. This study was designed to explore the expression and role which FOXG1 plays in human glioma. Methods： We detected the expression of FOXG1 by immunohistochemistry in glioma tissue samples. Following the down-regulation of FOXG1 in glioma cell lines by a specific short hairpin RNA, the function of FOXG1 in proliferation and apoptosis was assessed. Results： Glioma tissues exhibited notably higher expression of FOXG1 compared with control brain tissues and was positively corre- lated with histological malignancy. The down-regulation of FOXG1 in glioma cells led to a cell apoptosis in vitro. Cenclusion： The overexpression of FOXG1 is a novel glioma malignancy marker, and FOXG1 may be used as a new target in therapeutic strategies for human glioma.
基金supported by grants from the National Natural Science Foundation of China(31930045 and 81870899)the National Key R&D Program of China(2016YFA0501001)。
文摘The Wnt signaling pathway plays key roles in various developmental processes.Wnt5a,which activates the non-canonical pathway,has been shown to be particularly important for axon guidance and outgrowth as well as dendrite morphogenesis.However,the mechanism underlying the regulation of Wnt5a remains unclear.Here,through conditional disruption of Foxg1 in hippocampal progenitors and postmitotic neurons achieved by crossing Foxg1~(fl/fl)with Emx1-Cre and Nex-Cre,respectively,we found that Wnt5a rather than Wnt3a/Wnt2b was markedly upregulated.Overexpression of Foxg1 had the opposite effects along with decreased dendritic complexity and reduced mossy fibers in the hippocampus.We further demonstrated that FOXG1 directly repressed Wnt5a by binding to its promoter and one enhancer site.These results expand our knowledge of the interaction between Foxg1 and Wnt signaling and help elucidate the mechanisms underlying hippocampal development.
