雌激素受体β调控髓鞘损伤后少突胶质细胞发育的作用机制
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摘要
性别是影响少突胶质细胞(OLs)发育的因素之一,雌激素受体β(ERβ)可能参与了OLs的发育调控,但其作用机制尚未明确.为阐明ERβ如何调控OLs的发育,通过在原代培养的少突胶质细胞前体细胞(OPCs)中过表达相关基因,使用溶血性磷脂酰胆碱(LPC)诱导OLs损伤以及荧光素酶报告基因等方法,考察了OPCs中ERβ如何调节细胞的分化以及ERβ受到哪些因素的调控.结果显示:过表达ERβ基因能够促进OPCs分化;LPC诱导损伤后,少突胶质细胞转录因子-2(Olig2)基因与ERβ的表达水平呈负相关,且过表达Olig2能够抑制OPCs中ERβ的表达水平;同时,LPC处理可诱导miRNA mmu-miR-219-2的表达,且mmu-miR-219-2能够直接与ERβ基因的3’-非翻译区结合并抑制其表达;而ERβ则通过与G蛋白偶联受体17(Gpr17)基因的启动子结合抑制Gpr17基因的表达,从而促进OPCs的成熟.综上,Olig2/mmu-miR-219-2/ERβ/Gpr17这一调控通路可能参与了OLs发育过程的调控,有望为临床上脱髓鞘疾病的治疗提供新的靶点.
Gender is one of the factors influencing the development of oligodendrocytes(OLs),and the estrogen receptorβ (ERβ )may play a role in this regulation.However,the underlying mechanism remains unclear.To reveal the mechanism about how ERβ regulates the development of OLs,we used several methods including overexpressing some related genes in the primary culture of oligodendrocyte precursor cells(OPCs),inducing injury in OLs by lysolecithin(LPC)treatment and dual-luciferase reporter assays,to investigate the effect of ERβ in regulating OPCs differentiation and the factors that modulate the expression of ERβ .The results showed that overexpression of ERβ gene promoted differentiation of the oligodendrocyte precursor cells.Upon LPC injury,the expression levels of the oligodendrocyte transcription factor-2(Olig2)gene and ERβ were negatively correlated,and overexpression of Olig2 inhibited the level of ERβ in the OPCs.Meanwhile,the expression level of miRNA mmu-miR-219-2 was induced by LPC injury,and mmu-miR-219-2 inhibited the expression level of ERβ through a direct interaction with its 3'-untranslation region.Furthermore,ERβ bound to the promoter region of the G-protein coupled receptor 17(Gpr17)gene and reduced its expression,accelerating the maturation of the OPCs.Taking together,our current study revealed an Olig2/mmu-miR-219-2/ERβ /Gpr17 signaling pathway that participated in the regulation of OLs development,which might potentially provide a novel therapeutic target for the demyelination diseases in clinical practice.
Gender is one of the factors influencing the development of oligodendrocytes(OLs),and the estrogen receptorβ (ERβ )may play a role in this regulation.However,the underlying mechanism remains unclear.To reveal the mechanism about how ERβ regulates the development of OLs,we used several methods including overexpressing some related genes in the primary culture of oligodendrocyte precursor cells(OPCs),inducing injury in OLs by lysolecithin(LPC)treatment and dual-luciferase reporter assays,to investigate the effect of ERβ in regulating OPCs differentiation and the factors that modulate the expression of ERβ .The results showed that overexpression of ERβ gene promoted differentiation of the oligodendrocyte precursor cells.Upon LPC injury,the expression levels of the oligodendrocyte transcription factor-2(Olig2)gene and ERβ were negatively correlated,and overexpression of Olig2 inhibited the level of ERβ in the OPCs.Meanwhile,the expression level of miRNA mmu-miR-219-2 was induced by LPC injury,and mmu-miR-219-2 inhibited the expression level of ERβ through a direct interaction with its 3'-untranslation region.Furthermore,ERβ bound to the promoter region of the G-protein coupled receptor 17(Gpr17)gene and reduced its expression,accelerating the maturation of the OPCs.Taking together,our current study revealed an Olig2/mmu-miR-219-2/ERβ /Gpr17 signaling pathway that participated in the regulation of OLs development,which might potentially provide a novel therapeutic target for the demyelination diseases in clinical practice.
引文
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[14]SWAMYDAS M,BESSERT D,SKOFF R.Sexual dimorphism of oligodendrocytes is mediated by differential regulation of signaling pathways[J].Journal of Neuroscience Research,2009,87(15):3306-3319.
[15]BARRATT H E,BUDNICK H C,PARRA R,et al.Tamoxifen promotes differentiation of oligodendrocyte progenitors in vitro[J].Neuroscience,2016,319:146-154.
[16]LABOMBARDA F,GONZALEZ S,LIMA A,et al.Progesterone attenuates astro-and microgliosis and enhances oligodendrocyte differentiation following spinal cord injury[J].Experimental Neurology,2011,231(1):135-146.
[17]CERGHET M,SKOFF R P,BESSERT D,et al.Proliferation and death of oligodendrocytes and myelin proteins are differentially regulated in male and female rodents[J].The Journal of Neuroscience,2006,26(5):1439-1447.
[18]LI W W,PENDERIS J,ZHAO C,et al.Females remyelinate more efficiently than males following demyelination in the aged but not young adult CNS[J].Experimental Neurology,2006,202(1):250-254.
[19]HAGHMORAD D,SALEHIPOUR Z,NOSRATABADIR,et al.Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice[J].Journal of Immunotoxicology,2016,13(6):885-896.
[20]KHALAJ A J,YOON J,NAKAI J,et al.Estrogen receptor(ER)βexpression in oligodendrocytes is required for attenuation of clinical disease by an ERβligand[J].Proceedings of the National Academy of Sciences of the United States of America,2013,110(47):19125-19130.
[21]KIM S,LIVA S M,DALAL M A,et al.Estriol ameliorates autoimmune demyelinating disease:implications for multiple sclerosis[J].Neurology,1999,52(6):1230-1238.
[22]AIRAS L.Hormonal and gender-related immune changes in multiple sclerosis[J].Acta Neurologica Scandinavica,2015,132(199):62-70.
[23]BENEDEK G,ZHANG J,BODHANKAR S,et al.Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis[J].Journal of Neuroimmunology,2016,293:45-53.
[24]ZHANG Z,CERGHET M,MULLINS C,et al.Comparison of in vivo andin vitro subcellular localization of estrogen receptorsαandβin oligodendrocytes[J].Journal of Neurochemistry,2004,89(3):674-684.
[25]KUMAR S,PATEL R,MOORE S,et al.Estrogen receptorβligand therapy activates PI3K/Akt/mTORsignaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis[J].Neurobiology of Disease,2013,56:131-144.
[2]FRANKLIN R J.Remyelination of the demyelinated CNS:the case for and against transplantation of central,peripheral and olfactory glia[J].Brain Research Bulletin,2002,57(6):827-832.
[3]FANCY S P,CHAN J R,BARANZINI S E,et al.Myelin regeneration:a recapitulation of development?[J]Annual Review of Neuroscience,2011,34:21-43.
[4]KANG S H,FUKAYA M,YANG J K,et al.NG2+CNSglial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration[J].Neuron,2010,68(4):668-681.
[5]TRIPATHI R B,RIVERS L E,YOUNG K M,et al.NG2glia generate new oligodendrocytes but few astrocytes in a murine experimental autoimmune encephalomyelitis model of demyelinating disease[J].The Journal of Neuroscience,2010,30(48):16383-16390.
[6]FRANKLIN R J M,FFRENCH-CONSTANT C.Remyelination in the CNS:from biology to therapy[J].Nature Reviews Neuroscience,2008,9(11):839-855.
[7]PFEIFFER S E,WARRINGTON A E,BANSAL R.The oligodendrocyte and its many cellular processes[J].Trends in Cell Biology,1993,3(6):191-197.
[8]BERGER J,MOSER H W,FORSS-PETTER S.Leukodystrophies:recent developments in genetics,molecular biology,pathogenesis and treatment[J].Current Opinion in Neurology,2001,14(3):305-312.
[9]TRAPP B D,PETERSON J,RANSOHOFF R M,et al.Axonal transection in the lesions of multiple sclerosis[J].The New England Journal of Medicine,1998,338(5):278-285.
[10]OU Z,SUN Y,LIN L,et al.Olig2-targeted G-proteincoupled receptor Gpr17regulates oligodendrocyte survival in response to lysolecithin-induced demyelination[J].The Journal of Neuroscience,2016,36(41):10560-10573.
[11]LAITMAN B M,ASP L,MARIANI J N,et al.The transcriptional activator Krüppel-like factor-6is required for CNS myelination[J].PLoS Biology,2016,14(5):e1002467.
[12]DOI T,OGATA T,YAMAUCHI J,et al.Chd7collaborates with Sox2 to regulate activation of oligodendrocyte precursor cells after spinal cord injury[J].The Journal of Neuroscience,2017,37(43):10290-10309.
[13]HE D Y,MARIE C,ZHAO C T,et al.Chd7cooperates with Sox10and regulates the onset of CNS myelination and remyelination[J].Nature Neuroscience,2016,19(5):678-689.
[14]SWAMYDAS M,BESSERT D,SKOFF R.Sexual dimorphism of oligodendrocytes is mediated by differential regulation of signaling pathways[J].Journal of Neuroscience Research,2009,87(15):3306-3319.
[15]BARRATT H E,BUDNICK H C,PARRA R,et al.Tamoxifen promotes differentiation of oligodendrocyte progenitors in vitro[J].Neuroscience,2016,319:146-154.
[16]LABOMBARDA F,GONZALEZ S,LIMA A,et al.Progesterone attenuates astro-and microgliosis and enhances oligodendrocyte differentiation following spinal cord injury[J].Experimental Neurology,2011,231(1):135-146.
[17]CERGHET M,SKOFF R P,BESSERT D,et al.Proliferation and death of oligodendrocytes and myelin proteins are differentially regulated in male and female rodents[J].The Journal of Neuroscience,2006,26(5):1439-1447.
[18]LI W W,PENDERIS J,ZHAO C,et al.Females remyelinate more efficiently than males following demyelination in the aged but not young adult CNS[J].Experimental Neurology,2006,202(1):250-254.
[19]HAGHMORAD D,SALEHIPOUR Z,NOSRATABADIR,et al.Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice[J].Journal of Immunotoxicology,2016,13(6):885-896.
[20]KHALAJ A J,YOON J,NAKAI J,et al.Estrogen receptor(ER)βexpression in oligodendrocytes is required for attenuation of clinical disease by an ERβligand[J].Proceedings of the National Academy of Sciences of the United States of America,2013,110(47):19125-19130.
[21]KIM S,LIVA S M,DALAL M A,et al.Estriol ameliorates autoimmune demyelinating disease:implications for multiple sclerosis[J].Neurology,1999,52(6):1230-1238.
[22]AIRAS L.Hormonal and gender-related immune changes in multiple sclerosis[J].Acta Neurologica Scandinavica,2015,132(199):62-70.
[23]BENEDEK G,ZHANG J,BODHANKAR S,et al.Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis[J].Journal of Neuroimmunology,2016,293:45-53.
[24]ZHANG Z,CERGHET M,MULLINS C,et al.Comparison of in vivo andin vitro subcellular localization of estrogen receptorsαandβin oligodendrocytes[J].Journal of Neurochemistry,2004,89(3):674-684.
[25]KUMAR S,PATEL R,MOORE S,et al.Estrogen receptorβligand therapy activates PI3K/Akt/mTORsignaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis[J].Neurobiology of Disease,2013,56:131-144.