Lingo-1抑制髓鞘再生的分子机制及临床应用前景
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摘要
Lingo-1(leucine-rich repeat and Ig domain containing,Nogo receptor-interacting protein1)是一种选择性表达于中枢神经系统的跨膜蛋白。目前,针对髓鞘再生过程的研究发现,在中枢神经系统损伤后出现高表达Lingo-1,从而抑制损伤区少突胶质前体细胞(oligodendrocyte progenitor cells,OPCs)的分化并降低神经元的存活率,最终抑制损伤神经元的髓鞘再生。由此提示,Lingo-1可能成为促进损伤后神经修复的重要新靶点。该文就近年来关于Lingo-1对中枢神经系统髓鞘再生影响的研究及其作用机制作一简单综述。
Leucine-rich repeat and Ig domain containing, Nogo receptor-interacting protein 1(Lingo-1) is a transmembrane protein selectively expressed in central nervous system. Recent studies on remyelination have observed high expression of Lingo-1 after central nervous system damage, inhibiting remyelination of damaged neurons by inhibiting differentiation of oligodendrocyte progenitor cells(OPCs) and reducing survival rate of neurons. Current researches indicate that Lingo-1 can be used as an important new target to promote nerve repair after damage. This review focuses on the functionary mechanism of Lingo-1 in the remyelination of central nervous system.
Leucine-rich repeat and Ig domain containing, Nogo receptor-interacting protein 1(Lingo-1) is a transmembrane protein selectively expressed in central nervous system. Recent studies on remyelination have observed high expression of Lingo-1 after central nervous system damage, inhibiting remyelination of damaged neurons by inhibiting differentiation of oligodendrocyte progenitor cells(OPCs) and reducing survival rate of neurons. Current researches indicate that Lingo-1 can be used as an important new target to promote nerve repair after damage. This review focuses on the functionary mechanism of Lingo-1 in the remyelination of central nervous system.
引文
1 Barateiro A,Fernandes A.Temporal oligodendrocyte lineage progression:in vitro models of proliferation,differentiation and myelination.Biochim Biophys Acta 2014;1843(9):1917-29.
2 Mi S,Miller RH,Tang W,Lee X,Hu B,Wu W,et al.Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells.Ann Neurol 2009;65(3):304-15.
3 Jepson S,Vought B,Gross CH,Gan L,Austen D,Frantz JD,et al.LINGO-1,a transmembrane signaling protein,inhibits oligodendrocyte differentiation and myelination through intercellular selfinteractions.J Biol Chem 2012;287(26):22184-95.
4 Llorens F,Gil V,Iraola S,Carim-Todd L,Marti E,Estivill X,et al.Developmental analysis of Lingo-1/Lern1 protein expression in the mouse brain:interaction of its intracellular domain with Myt1l.Dev Neurobiol 2008;68(4):521-41.
5 Mi S,Miller RH,Lee X,Scott ML,Shulag-Morskaya S,Shao Z,et al.LINGO-1 negatively regulates myelination by oligodendrocytes.Nat Neurosci 2005;8(6):745-51.
6 Mosyak L,Wood A,Dwyer B,Buddha M,Johnson M,Aulabaugh A,et al.The structure of the Lingo-1 ectodomain,a module implicated in central nervous system repair inhibition.J Biol Chem 2006;281(47):36378-90.
7 Agundez JA,Jimenez-Jimenez FJ,Alonso-Navarro H,GarciaMartin E.The potential of LINGO-1 as a therapeutic target for essential tremor.Expert Opin Ther Targets 2015;19(8):1139-48.
8 Zhang Z,Xu X,Xiang Z,Yu Z,Feng J,He C.LINGO-1 receptor promotes neuronal apoptosis by inhibiting WNK3 kinase activity.J Biol Chem 2013;288(17):12152-60.
9 Mi S,Lee X,Shao Z,Thill G,Ji B,Relton J,et al.LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex.Nat Neurosci 2004;7(3):221-8.
10 Mi S,Pepinsky RB,Cadavid D.Blocking LINGO-1 as a therapy to promote CNS repair:from concept to the clinic.CNS Drugs2013;27(7):493-503.
11 Lee X,Yang Z,Shao Z,Rosenberg SS,Levesque M,Pepinsky RB,et al.NGF regulates the expression of axonal LINGO-1to inhibit oligodendrocyte differentiation and myelination.J Neurosci 2007;27(1):220-5.
12 Xing HY,Meng EY,Xia YP,Peng H.Effect of retinoic acid on expression of LINGO-1 and neural regeneration after cerebral ischemia.J Huazhong Univ Sci Technolog Med Sci 2015;35(1):54-7.
13 Blakemore WF,Franklin RJ.Remyelination in experimental models of toxin-induced demyelination.Curr Top Microbiol Immunol 2008;318:193-212.
14 Mi S,Hu B,Hahm K,Luo Y,Kam Hui ES,Yuan Q,et al.LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis.Nat Med 2007;13(10):1228-33.
15 Mathis C,Schroter A,Thallmair M,Schwab ME.Nogo-a regulates neural precursor migration in the embryonic mouse cortex.Cereb Cortex 2010;20(10):2380-90.
16 Hutson TH,Foster E,Dawes JM,Hindges R,Yanez-Munoz RJ,Moon LD.Lentiviral vectors encoding short hairpin RNAs efficiently transduce and knockdown LINGO-1 but induce an interferon response and cytotoxicity in central nervous system neurones.J Gene Med 2012;14(5):299-315.
17 Rother S,Meister G.Small RNAs derived from longer noncoding RNAs.Biochimie 2011;93(11):1905-15.
18 Cen J,Wu H,Wang J,Ren X,Zhang H,Wang J,et al.Local injection of lentivirus encoding LINGO-1-sh RNA promotes functional recovery in rats with complete spinal cord transection.Spine 2013;38(19):1632-9.
19 Ji B,Li M,Wu WT,Yick LW,Lee X,Shao Z,et al.LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury.Mo Cell Neurosci 2006;33(3):311-20.
20 Inoue H,Lin L,Lee X,Saho Z,Mendes S,Snodgrass-Belt P,et al.Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival,structure,and function of dopaminergic neurons in Parkinson’s disease models.Proc Natl Acad Sci USA 2007;104(36):14430-5.
21 Zhang Y,Zhang YP,Pepinsky B,Huang G,Shields LB,Shields CB,et al.Inhibition of LINGO-1 promotes functional recovery after experimental spinal cord demyelination.Exp Neurol 2015;266:68-73.
22 Sha M,Sandrock A,Miller RH.LINGO-1 and its role in CNS repair.Int J Biochem Cell Biol 2008;40(10):1971-8.
23 Delay C,Tremblay C,Brochu E,Paris-Robidas S,Emond V,Rajput AH,et al.Increased LINGO1 in the cerebellum of essential tremor patients.Mov Disord 2014;29(13):1637-47.
24 Bossemeyer D.WNK kinases,a novel protein kinase subfamily in multi-cellular organisms.Oncogene 2001;20(39):5562-9.
25 Satoh J,Tabunoki H,Yamamura T,Arima K,Konno H.TROY and LINGO-1 expression in astrocytes and macrophages/microglia in multiple sclerosis lesions.Neuropathol Appl Neurobiol 2007;33(1):99-107.
26 Barrette B,Vallieres N,Dube M,Lacroix S.Expression profile of receptors for myelin-associated inhibitors of axonal regeneration in the intact and injured mouse central nervous system.Mol Cell Neurosci 2007;34(4):519-38.
27 Zhao XH,Jin WL,Ju G.An in vitro study on the involvement of LINGO-1 and Rho GTPases in Nogo-A regulated differentiation of oligodendrocyte precursor cells.Mol Cell Neurosci 2007;36(2):260-9.
28 Liang X,Draghi NA,Resh MD.Signaling from integrins to Fyn to Rho family GTPases regulates morphologic differentiation of oligodendrocytes.J Neurosci 2004;24(32):7140-9.
29 Sperber BR,Mc Morris FA.Fyn tyrosine kinase regulates oligodendroglial cell development but is not required for morphological differentiation of oligodendrocytes.J Neurosci Res 2001;63(4):303-12.
30 Park JB,Yiu G,Kaneko S,Wang J,Chang J,He XL,et al.A TNF receptor family member,TROY,is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors.Neuron 2005;45(3):345-51.
31 Lee X,Shao Z,Sheng G,Pepinsky B,Mi S.LINGO-1 regulates oligodendrocyte differentiation by inhibiting Erb B2 translocation and activation in lipid rafts.Mol Cell Neurosci 2014;60:36-42.
32 Fox IJ,Kornblum HI.Developmental profile of Erb B receptors in murine central nervous system:implications for functional interactions.J Neurosci Res 2005;79(5):584-97.
33 Sussman CR,Vartanian T,Miller RH.The Erb B4 neuregulin receptor mediates suppression of oligodendrocyte maturation.J Neurosci 2005;25(24):5757-62.
34 Park SK,Miller R,Krane I,Vartanian T.The erb B2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes.J Cell Biol 2001;154(6):1245-58.
35 Makinodan M,Rosen KM,Ito S,Corfas G.A critical period for social experience-dependent oligodendrocyte maturation and myelination.Science 2012;337(6100):1357-60.
36 Chan JR,Watkins TA,Cosgaya JM,Zhang C,Chen L,Reichardt LF,,et al.NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes.Neuron 2004;43(2):183-91.
37 Chin PC,Majdzadeh N,D’Mello SR.Inhibition of GSK3beta is a common event in neuroprotection by different survival factors.Brain Res Mol Brain Res 2005;137(1/2):193-201.
38 Zhao XH,Jin WL,Wu J,Mi S,Ju G.Inactivation of glycogen synthase kinase-3beta and up-regulation of LINGO-1 are involved in LINGO-1 antagonist regulated survival of cerebellar granular neurons.Cell Mol Neurobiol 2008;28(5):727-35.
39 Yang T,Zhao K,Shu H,Chen X,Cheng J,Li S,et al.The Nogo receptor inhibits proliferation,migration and axonal extension by transcriptionally regulating WNK1 in PC12 cells.Neuroreport2017;28(9):533-9.
40 Zhang Z,Xu X,Zhang Y,Zhou J,Yu Z,He C.LINGO-1 interacts with WNK1 to regulate nogo-induced inhibition of neurite extension.J Biol Chem 2009;284(23):15717-28.
41 Kotter MR,Zhao C,Rooijen NV,Franklin RJM.Macrophagedepletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression.Neurobiol Dis2005;18(1):166-75.
42 Zhang L,Zhang HT,Hong SQ,Ma X,Jiang XD,Xu RX.Cografted Wharton’s jelly cells-derived neurospheres and BDNF promote functional recovery after rat spinal cord transection.Neurochem Res 2009;34(11):2030-9.
2 Mi S,Miller RH,Tang W,Lee X,Hu B,Wu W,et al.Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells.Ann Neurol 2009;65(3):304-15.
3 Jepson S,Vought B,Gross CH,Gan L,Austen D,Frantz JD,et al.LINGO-1,a transmembrane signaling protein,inhibits oligodendrocyte differentiation and myelination through intercellular selfinteractions.J Biol Chem 2012;287(26):22184-95.
4 Llorens F,Gil V,Iraola S,Carim-Todd L,Marti E,Estivill X,et al.Developmental analysis of Lingo-1/Lern1 protein expression in the mouse brain:interaction of its intracellular domain with Myt1l.Dev Neurobiol 2008;68(4):521-41.
5 Mi S,Miller RH,Lee X,Scott ML,Shulag-Morskaya S,Shao Z,et al.LINGO-1 negatively regulates myelination by oligodendrocytes.Nat Neurosci 2005;8(6):745-51.
6 Mosyak L,Wood A,Dwyer B,Buddha M,Johnson M,Aulabaugh A,et al.The structure of the Lingo-1 ectodomain,a module implicated in central nervous system repair inhibition.J Biol Chem 2006;281(47):36378-90.
7 Agundez JA,Jimenez-Jimenez FJ,Alonso-Navarro H,GarciaMartin E.The potential of LINGO-1 as a therapeutic target for essential tremor.Expert Opin Ther Targets 2015;19(8):1139-48.
8 Zhang Z,Xu X,Xiang Z,Yu Z,Feng J,He C.LINGO-1 receptor promotes neuronal apoptosis by inhibiting WNK3 kinase activity.J Biol Chem 2013;288(17):12152-60.
9 Mi S,Lee X,Shao Z,Thill G,Ji B,Relton J,et al.LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex.Nat Neurosci 2004;7(3):221-8.
10 Mi S,Pepinsky RB,Cadavid D.Blocking LINGO-1 as a therapy to promote CNS repair:from concept to the clinic.CNS Drugs2013;27(7):493-503.
11 Lee X,Yang Z,Shao Z,Rosenberg SS,Levesque M,Pepinsky RB,et al.NGF regulates the expression of axonal LINGO-1to inhibit oligodendrocyte differentiation and myelination.J Neurosci 2007;27(1):220-5.
12 Xing HY,Meng EY,Xia YP,Peng H.Effect of retinoic acid on expression of LINGO-1 and neural regeneration after cerebral ischemia.J Huazhong Univ Sci Technolog Med Sci 2015;35(1):54-7.
13 Blakemore WF,Franklin RJ.Remyelination in experimental models of toxin-induced demyelination.Curr Top Microbiol Immunol 2008;318:193-212.
14 Mi S,Hu B,Hahm K,Luo Y,Kam Hui ES,Yuan Q,et al.LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis.Nat Med 2007;13(10):1228-33.
15 Mathis C,Schroter A,Thallmair M,Schwab ME.Nogo-a regulates neural precursor migration in the embryonic mouse cortex.Cereb Cortex 2010;20(10):2380-90.
16 Hutson TH,Foster E,Dawes JM,Hindges R,Yanez-Munoz RJ,Moon LD.Lentiviral vectors encoding short hairpin RNAs efficiently transduce and knockdown LINGO-1 but induce an interferon response and cytotoxicity in central nervous system neurones.J Gene Med 2012;14(5):299-315.
17 Rother S,Meister G.Small RNAs derived from longer noncoding RNAs.Biochimie 2011;93(11):1905-15.
18 Cen J,Wu H,Wang J,Ren X,Zhang H,Wang J,et al.Local injection of lentivirus encoding LINGO-1-sh RNA promotes functional recovery in rats with complete spinal cord transection.Spine 2013;38(19):1632-9.
19 Ji B,Li M,Wu WT,Yick LW,Lee X,Shao Z,et al.LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury.Mo Cell Neurosci 2006;33(3):311-20.
20 Inoue H,Lin L,Lee X,Saho Z,Mendes S,Snodgrass-Belt P,et al.Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival,structure,and function of dopaminergic neurons in Parkinson’s disease models.Proc Natl Acad Sci USA 2007;104(36):14430-5.
21 Zhang Y,Zhang YP,Pepinsky B,Huang G,Shields LB,Shields CB,et al.Inhibition of LINGO-1 promotes functional recovery after experimental spinal cord demyelination.Exp Neurol 2015;266:68-73.
22 Sha M,Sandrock A,Miller RH.LINGO-1 and its role in CNS repair.Int J Biochem Cell Biol 2008;40(10):1971-8.
23 Delay C,Tremblay C,Brochu E,Paris-Robidas S,Emond V,Rajput AH,et al.Increased LINGO1 in the cerebellum of essential tremor patients.Mov Disord 2014;29(13):1637-47.
24 Bossemeyer D.WNK kinases,a novel protein kinase subfamily in multi-cellular organisms.Oncogene 2001;20(39):5562-9.
25 Satoh J,Tabunoki H,Yamamura T,Arima K,Konno H.TROY and LINGO-1 expression in astrocytes and macrophages/microglia in multiple sclerosis lesions.Neuropathol Appl Neurobiol 2007;33(1):99-107.
26 Barrette B,Vallieres N,Dube M,Lacroix S.Expression profile of receptors for myelin-associated inhibitors of axonal regeneration in the intact and injured mouse central nervous system.Mol Cell Neurosci 2007;34(4):519-38.
27 Zhao XH,Jin WL,Ju G.An in vitro study on the involvement of LINGO-1 and Rho GTPases in Nogo-A regulated differentiation of oligodendrocyte precursor cells.Mol Cell Neurosci 2007;36(2):260-9.
28 Liang X,Draghi NA,Resh MD.Signaling from integrins to Fyn to Rho family GTPases regulates morphologic differentiation of oligodendrocytes.J Neurosci 2004;24(32):7140-9.
29 Sperber BR,Mc Morris FA.Fyn tyrosine kinase regulates oligodendroglial cell development but is not required for morphological differentiation of oligodendrocytes.J Neurosci Res 2001;63(4):303-12.
30 Park JB,Yiu G,Kaneko S,Wang J,Chang J,He XL,et al.A TNF receptor family member,TROY,is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors.Neuron 2005;45(3):345-51.
31 Lee X,Shao Z,Sheng G,Pepinsky B,Mi S.LINGO-1 regulates oligodendrocyte differentiation by inhibiting Erb B2 translocation and activation in lipid rafts.Mol Cell Neurosci 2014;60:36-42.
32 Fox IJ,Kornblum HI.Developmental profile of Erb B receptors in murine central nervous system:implications for functional interactions.J Neurosci Res 2005;79(5):584-97.
33 Sussman CR,Vartanian T,Miller RH.The Erb B4 neuregulin receptor mediates suppression of oligodendrocyte maturation.J Neurosci 2005;25(24):5757-62.
34 Park SK,Miller R,Krane I,Vartanian T.The erb B2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes.J Cell Biol 2001;154(6):1245-58.
35 Makinodan M,Rosen KM,Ito S,Corfas G.A critical period for social experience-dependent oligodendrocyte maturation and myelination.Science 2012;337(6100):1357-60.
36 Chan JR,Watkins TA,Cosgaya JM,Zhang C,Chen L,Reichardt LF,,et al.NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes.Neuron 2004;43(2):183-91.
37 Chin PC,Majdzadeh N,D’Mello SR.Inhibition of GSK3beta is a common event in neuroprotection by different survival factors.Brain Res Mol Brain Res 2005;137(1/2):193-201.
38 Zhao XH,Jin WL,Wu J,Mi S,Ju G.Inactivation of glycogen synthase kinase-3beta and up-regulation of LINGO-1 are involved in LINGO-1 antagonist regulated survival of cerebellar granular neurons.Cell Mol Neurobiol 2008;28(5):727-35.
39 Yang T,Zhao K,Shu H,Chen X,Cheng J,Li S,et al.The Nogo receptor inhibits proliferation,migration and axonal extension by transcriptionally regulating WNK1 in PC12 cells.Neuroreport2017;28(9):533-9.
40 Zhang Z,Xu X,Zhang Y,Zhou J,Yu Z,He C.LINGO-1 interacts with WNK1 to regulate nogo-induced inhibition of neurite extension.J Biol Chem 2009;284(23):15717-28.
41 Kotter MR,Zhao C,Rooijen NV,Franklin RJM.Macrophagedepletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression.Neurobiol Dis2005;18(1):166-75.
42 Zhang L,Zhang HT,Hong SQ,Ma X,Jiang XD,Xu RX.Cografted Wharton’s jelly cells-derived neurospheres and BDNF promote functional recovery after rat spinal cord transection.Neurochem Res 2009;34(11):2030-9.