Circular RNAs(circRNAs)regulate gene expression and participate in various biological and pathological processes.However,little is known about the effects of specific circRNAs on T helper cell 17(Th17)differentiation ...Circular RNAs(circRNAs)regulate gene expression and participate in various biological and pathological processes.However,little is known about the effects of specific circRNAs on T helper cell 17(Th17)differentiation and related autoimmune diseases,such as multiple sclerosis(MS).Here,using transcriptome microarray analysis at different stages of experimental autoimmune encephalomyelitis(EAE),we identified the EAE progression-related circINPP4B,which showed upregulated expression in Th17 cells from mice with EAE and during Th17 differentiation in vitro.Silencing of circINPP4B inhibited Th17 differentiation and alleviated EAE,characterized by less demyelination and Th17 infiltration in the spinal cord.Mechanistically,circINPP4B served as a sponge that directly targeted miR-30a to regulate Th17 differentiation.Furthermore,circINPP4B levels were associated with the developing phases of clinical relapsing-remitting MS patients.Our results indicate that circINPP4B plays an important role in promoting Th17 differentiation and progression of EAE by targeting miR-30a,which provides a potential diagnostic and therapeutic target for Th17-mediated MS.展开更多
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
基金This research was supported by the National Natural Science Foundation of China(81771337,81271345)The National Key R&D Program of China(2017YFA0104202)+3 种基金The Natural Science Foundation of Jiangsu Province(BK20161174)the 333 Project of Jiangsu ProvinceThe Xuzhou Basic Research Science and Technology Project(KC19059)Xuzhou Medical University Scientific Research Fund for Talents.
文摘Circular RNAs(circRNAs)regulate gene expression and participate in various biological and pathological processes.However,little is known about the effects of specific circRNAs on T helper cell 17(Th17)differentiation and related autoimmune diseases,such as multiple sclerosis(MS).Here,using transcriptome microarray analysis at different stages of experimental autoimmune encephalomyelitis(EAE),we identified the EAE progression-related circINPP4B,which showed upregulated expression in Th17 cells from mice with EAE and during Th17 differentiation in vitro.Silencing of circINPP4B inhibited Th17 differentiation and alleviated EAE,characterized by less demyelination and Th17 infiltration in the spinal cord.Mechanistically,circINPP4B served as a sponge that directly targeted miR-30a to regulate Th17 differentiation.Furthermore,circINPP4B levels were associated with the developing phases of clinical relapsing-remitting MS patients.Our results indicate that circINPP4B plays an important role in promoting Th17 differentiation and progression of EAE by targeting miR-30a,which provides a potential diagnostic and therapeutic target for Th17-mediated MS.
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.