RGMa在实验性自身免疫性脑脊髓炎中的表达的实验研究
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摘要
目的多发性硬化是一种致残率较高的中枢神经系统炎性脱髓鞘性疾病。在病理上主要表现为位于中枢神经系统白质的多发性炎性脱髓鞘和轴突损伤,而后者又被认为是多发性硬化致残的主要原因。中枢神经再生是近年来神经康复的难点和热点,而轴突生长抑制因子被认为是导致中枢神经再生困难的主要原因。近年来通过在脊髓损伤和脑损伤模型中的研究发现RGM (repulsive guidance molecule)不仅是一种轴突导向分子,还是一种对中枢神经系统轴突再生具有抑制作用的膜蛋白。RGM参与了中枢神经系统损伤后轴突生长抑制性信号的传递,在轴突再生过程中起关键作用。近年来研究发现,多发性硬化早期存在轴索损伤,RGM在多发性硬化的轴索损伤及修复中是否扮演着重要的角色?迄今尚未见文献报道。本实验拟通过建立急﹑慢性多发性硬化模型,检测RGM在实验性自身免疫性脑脊髓炎(EAE)大鼠脑和脊髓中的表达规律,从而推测RGM在多发性硬化疾病的发生发展和转归中的可能作用和机制。
方法运用豚鼠脊髓匀浆和完全弗氏佐剂混合制成油包水抗原乳剂,并注射百日咳杆菌建立EAE大鼠模型。通过HE染色来判断模型成功与否。分别设立正常对照组﹑EAE急性组﹑EAE慢性完全缓解组和EAE慢性部分缓解组,通过神经功能缺损评分判断大鼠临床症状。通过RT-PCR来检测RGMa mRNA在各个组中的表达规律,并通过免疫组化来检测膜蛋白RGMa在各个组脑和脊髓中的表达规律。
结果在正常对照组和EAE各组,RGMa mRNA在急性组表达量最高,在慢性组表达量较急性组降低,但仍高于正常对照组。RGMa蛋白在正常对照组主要表达在脑皮质、脊髓灰质﹑白质纤维束、少突胶质样细胞、脉络丛、海马和一些内皮细胞;在EAE急性组RGMa蛋白阳性表达明显较对照组增高,RGMa阳性表达主要聚集在病灶和病灶周围的区域,如血管周围浸润的炎性细胞和病灶周围增生的星形胶质细胞;在EAE慢性组,RGMa蛋白的表达量较急性组稍有降低,但仍高于正常组,主要表达在病灶周围大量增生的星形胶质细胞。
结论RGMa mRNA和RGMa蛋白在EAE急性期组的表达明显增高,在EAE慢性组其表达量降低但仍高于正常对照组,提示RGMa与多发性硬化疾病的发生发展密切相关。RGMa蛋白主要表达在少突胶质细胞,星形胶质细胞等几种大量表达轴突生长抑制因子的组织和细胞上,提示RGMa很有可能作为一种轴突生长抑制因子在多发性硬化中起作用。
Objective Multiple sclerosis (MS) is a kind of inflammatory demyelinating diseases in central nervous system (CNS) with high disability. In pathology, it presents as multiple inflammatory demyelinating lesions and axonal injury in white matter of CNS and the latter is the main reason of disability of MS patients. In recent years, the regeneration of CNS has been the focus of nervous rehabilitation. The axonal growth inhibitors are considered to be one of the main factors causing the difficulty of CNS regeneration. Recently, the analyses of repulsive guidance molecule (RGM) expression in the model of spinal cord injury and brain injury indicate that RGM is not only an axonal guidance molecue and also an membrane protein limitating axonal growth of CNS. RGM participates and plays an important role in the transfer of axonal growth inhibitory signal after injury of CNS . However, no study has been reported about the RGM expression in multiple sclerosis. In our study, we analyzed the expression pattern of RGM in spinal cord and brain of rats in acute and chronic model of multiple sclerosis and speculated the possible function and mechanism of RGM in the occurrence, progress and prognosis of multiple sclerosis.
Methods Experimental autoimmune encephalomyelitis (EAE) was induced by a single 400-μl subcutaneous injection of the following emulsions in the footpad: guinea pig spinal cord homogenate (GPSCH) (50% w/v in saline) emulsified in an equal volume of Freund’s complete adjuvant (FCA) and 0.1 ml of Bordetella pertussis in the instep (approximately 4.0×109 live bacteria). The judgment of the model was done with HE stain. The rats were divided into four groups: the control, EAE acute group, EAE chronic group with complete remission and EAE chronic group with partial remission. Neurological deficits score was used to evaluate EAE. The Immunohistochemistry and double labeling of immunofluorescence were used to analyze the RGMa expression pattern in spinal cord and brain of rats in control and EAE groups. Reverse transcriptase Polymerase Chain Reaction (RT-PCR) was done to detect the expression of RGMa mRNA in the four groups.
Results In control group and EAE groups, the expression of RGMa mRNA was highest in EAE acute group and decreased in EAE chronic groups. In brain and spinal cord of control rats, RGMa immunoreactivity was detected on cortex, grey matter, white matter fibers, oligodendrocyte, choroid plexus, hippocampus and few endothelial cells. In EAE acute group, the RGMa immunopositive cells significantly elevated as compared to control and accumulated in lesions and peri-lesional areas such as inflammatory cells aroud vessels and astrocytes. In EAE chronic group, the RGMa immunopositive cells decreased as compared with EAE acute group but still higher than the control and mainly expressed in the hyperplastic astrocytes surrounding the lesions.
Conclusion The RGMa mRNA and RGMa protein were increased significantly in EAE acute group and decreased in EAE chronic groups but still higher than control group. It indicated that RGMa may play an important role in the onset and development of multiple sclerosis. RGMa Protein mainly expressed in the tissue or cells such as oligodendrocytes and astrocytes which greatly express axonal growth inhibitor. It indicated that RGMa may act as an axonal growth inhibitor in multiple sclerosis patients.
方法运用豚鼠脊髓匀浆和完全弗氏佐剂混合制成油包水抗原乳剂,并注射百日咳杆菌建立EAE大鼠模型。通过HE染色来判断模型成功与否。分别设立正常对照组﹑EAE急性组﹑EAE慢性完全缓解组和EAE慢性部分缓解组,通过神经功能缺损评分判断大鼠临床症状。通过RT-PCR来检测RGMa mRNA在各个组中的表达规律,并通过免疫组化来检测膜蛋白RGMa在各个组脑和脊髓中的表达规律。
结果在正常对照组和EAE各组,RGMa mRNA在急性组表达量最高,在慢性组表达量较急性组降低,但仍高于正常对照组。RGMa蛋白在正常对照组主要表达在脑皮质、脊髓灰质﹑白质纤维束、少突胶质样细胞、脉络丛、海马和一些内皮细胞;在EAE急性组RGMa蛋白阳性表达明显较对照组增高,RGMa阳性表达主要聚集在病灶和病灶周围的区域,如血管周围浸润的炎性细胞和病灶周围增生的星形胶质细胞;在EAE慢性组,RGMa蛋白的表达量较急性组稍有降低,但仍高于正常组,主要表达在病灶周围大量增生的星形胶质细胞。
结论RGMa mRNA和RGMa蛋白在EAE急性期组的表达明显增高,在EAE慢性组其表达量降低但仍高于正常对照组,提示RGMa与多发性硬化疾病的发生发展密切相关。RGMa蛋白主要表达在少突胶质细胞,星形胶质细胞等几种大量表达轴突生长抑制因子的组织和细胞上,提示RGMa很有可能作为一种轴突生长抑制因子在多发性硬化中起作用。
Objective Multiple sclerosis (MS) is a kind of inflammatory demyelinating diseases in central nervous system (CNS) with high disability. In pathology, it presents as multiple inflammatory demyelinating lesions and axonal injury in white matter of CNS and the latter is the main reason of disability of MS patients. In recent years, the regeneration of CNS has been the focus of nervous rehabilitation. The axonal growth inhibitors are considered to be one of the main factors causing the difficulty of CNS regeneration. Recently, the analyses of repulsive guidance molecule (RGM) expression in the model of spinal cord injury and brain injury indicate that RGM is not only an axonal guidance molecue and also an membrane protein limitating axonal growth of CNS. RGM participates and plays an important role in the transfer of axonal growth inhibitory signal after injury of CNS . However, no study has been reported about the RGM expression in multiple sclerosis. In our study, we analyzed the expression pattern of RGM in spinal cord and brain of rats in acute and chronic model of multiple sclerosis and speculated the possible function and mechanism of RGM in the occurrence, progress and prognosis of multiple sclerosis.
Methods Experimental autoimmune encephalomyelitis (EAE) was induced by a single 400-μl subcutaneous injection of the following emulsions in the footpad: guinea pig spinal cord homogenate (GPSCH) (50% w/v in saline) emulsified in an equal volume of Freund’s complete adjuvant (FCA) and 0.1 ml of Bordetella pertussis in the instep (approximately 4.0×109 live bacteria). The judgment of the model was done with HE stain. The rats were divided into four groups: the control, EAE acute group, EAE chronic group with complete remission and EAE chronic group with partial remission. Neurological deficits score was used to evaluate EAE. The Immunohistochemistry and double labeling of immunofluorescence were used to analyze the RGMa expression pattern in spinal cord and brain of rats in control and EAE groups. Reverse transcriptase Polymerase Chain Reaction (RT-PCR) was done to detect the expression of RGMa mRNA in the four groups.
Results In control group and EAE groups, the expression of RGMa mRNA was highest in EAE acute group and decreased in EAE chronic groups. In brain and spinal cord of control rats, RGMa immunoreactivity was detected on cortex, grey matter, white matter fibers, oligodendrocyte, choroid plexus, hippocampus and few endothelial cells. In EAE acute group, the RGMa immunopositive cells significantly elevated as compared to control and accumulated in lesions and peri-lesional areas such as inflammatory cells aroud vessels and astrocytes. In EAE chronic group, the RGMa immunopositive cells decreased as compared with EAE acute group but still higher than the control and mainly expressed in the hyperplastic astrocytes surrounding the lesions.
Conclusion The RGMa mRNA and RGMa protein were increased significantly in EAE acute group and decreased in EAE chronic groups but still higher than control group. It indicated that RGMa may play an important role in the onset and development of multiple sclerosis. RGMa Protein mainly expressed in the tissue or cells such as oligodendrocytes and astrocytes which greatly express axonal growth inhibitor. It indicated that RGMa may act as an axonal growth inhibitor in multiple sclerosis patients.
引文
[1] Schwab ME, Bartholdi D. Degeneration and regeneration of axons in the lesioned spinal cord [J]. Physiol Rev. 1996,76:319-70.
[2] McGee AW, Strittmatter SM. The Nogo-66 receptor: focusing myelin inhibition of axon regeneration [J].Trends Neurosci, 2003,26(4):193-8.
[3] GrandPre T,Nakamura F,Vartanian T,et al.Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein [J]. Nature,2000,409:341-346.
[4] Fournier AE,Grand PT,Strittmatter SM. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration [J]. Nature, 2001, 409(6818):341-346.
[5] Liu BP, Fournier A, GrandPre T, Strittmatter SM. Myelin-associated glycoprotein as a functional ligand for the Nogo receptor [J]. Science.2002,297:1190-1193.
[6] Domeniconi M,Cao I,Spencer T,et al. Myelin associated glycoprotein interacts with the Nogo receptor to neurite outgrowth [J]. Nature, 2002,35:283-290.
[7] Wang KC,Koprivica V,Kim JA,et al.Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand and that inhibits neurite outgrowth [J].Nature.2002,417:941-944.
[8] Wang KC,Kim J, Srivasankaran R,et al.P75 interacts with the Nogo receptor as a co-receptor for Nogo,MAG and OMgp [J].Nature.2002,420:74-78.
[9] Wong K,Ren XR,Huang YZ, et al.Sinal transduction in neuronal migration: GTPase activating proteins and the small GTPase Cdc42 in the Slit- Robo pathway [J].Cell,2001,107:209-221.
[10] Hata Katsuhiko, Fujitani Masashi, RGMa inhibition promotes axonal growth and recovery after spinal cord injury[J]. Cell Biology. 173(2006): 47-58
[11] Schwab, J.M., Conrad, S., Monnier, P.P., Julien, S., Mueller, B.K. & Schluesener, H.J., Spinal cord injury induces lesional expression pattern of the repulsive guidance molecule (RGM) [J]. Neurosci. 21(2005) 1569-1576.
[12] Fawcett, J.W. & Asher, R.A. (1999) The glial scar and central nervousrepair.Brain Res. Bull., 49, 377–391.
[13] Schwab,M.E.&Bartholdi,D.(1996) Degeneration and regeneration of axons in the lesioned spinal cord. Physiol.Rev., 76,319¨C37
[14] Philippe P.Monnler,Ana Slerra, Friedrich Bonhoeffer,et al.RGM is a repulsive guidance molecule for retinal axons[J].Nature 2002,26(419):392-395
[15] Oldekamp J, Kramer N,et al. Expression pattern of the repulsive guidance molecules RGM A, B and C during mouse development. Gene Expr Patterns. 2004,4(3):283-288
[16] Yamaguchi Y,Katoh H,Yasui H,et al. RhoA inhibits the nerve growth factor-induced Racl activation through Rho-associated kinase-dependent pathway[J].J Biol Chem,2001,276 (22):18977-l8983
[17] Sabine Conrad, Harald Genth,et al.Neogenin-RGMa Signaling at the Growth Cone Is BMP-Independent and Involves RhoA, Rock and PKC[J]. J Biol Chem. 2008: 29(1):105-113
[18]袁宝玉,秦新月,彭国光,PPAR-γ激动剂对急性EAE大鼠脑白质TNF-αmRNA表达的影响[J]。重庆医科大学学报,2007 32(1)。
[1] Schwab ME, Bartholdi D (1996) Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 76:319–370.
[2] Bray GM, Villegas-Perez MP, Vidal-Sanz M,Aguayo AJ (1987) The use of peripheral nerve grafts to enhance neuronal survival, promote growth and permit terminal reconnections in the central nervous system of adult rats. J Exp Biol 132:5–19.
[3] Horner PJ, Gage FH (2000) Regenerating the damaged central nervous system.Nature 407:963–970.
[4] Fournier AE , GrandPre T , Strittmatter SM. [J]. Nature , 2001 , 409(6818):341-346.
[5] Wang KC,Kim JA,Sivasankaran R,et al. [J]. Nature,2002,420(6911):74-77.
[6] Tang S, Woodhall RW, Shen YJ, DeBellard ME, Saffel JL, et al. 1997b. Soluble myelinassociated glycoprotein found in vivo inhibits axonal regeneration. Mol. Cell. Neurosci. 9:333–46
[7] Liu BP, Fournier A, GrandPr′e T, Strittmatter SM. 2002. Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297:1190–93
[8] Wang KC, Koprivica V, Kim JA, Srivasankaran R, Guo Y, et al. 2002a. Oligodendrocytemyelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:941–44
[9] Mikol DD, Gulcher JR, Stefansson K. 1990. The oligodendrocyte-myelin glycoprotein belongs to a distinct family of proteins and contains the HNK-1 carbohydrate. J. Cell Biol. 110:471–79
[10] Wang KC,Kim JA,Sivasankaran R,et al. [J]. Nature,2002,420(6911):74-77.
[11] Schnell L, Schwab ME. 1990. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343:269–72
[12] Bareyre FM, Haudenschild B, Schwab ME. Long-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord. J Neurosci 2002;22:7097–110
[13] GrandPre′T, Li S, Strittmatter SM. Nogo-66 receptor antagonist peptide a) promotes axonal regeneration. Nature 2002;417:547–51
[14] Philippe P.Monnler,Ana Slerra, Friedrich Bonhoeffer,et al.RGM is a repulsive guidance molecule for retinal axons.Nature 2002,26(419):392-395
[15] Oldekamp J, Kramer N,et al. Expression pattern of the repulsive guidance molecules RGM A, B and C during mouse development. Gene Expr Patterns. 2004,4(3):283-288
[16] Eiji Matsunaga,ServaneTauszig-Delamasure,et al.RGM and its receptor neogenin regulate neuronal survival.Nature Cell biology. 2004, 6(8):749- 755
[17] Toshihide Yamashita, Bernhard K Mueller,Katsuhiko Hata,et al. Neogenin and repulsive guidance molecule signaling in the central nervous system. Neurobiology, 2007,17 (1):29-34
[18] Schwab JM, Conrad S,et al.Spinal cord injury-induced lesional expression of the repulsive guidance molecule (RGM). Eur J Neurosci. 2005,21(6):1569-1576
[19] Swiercz J, Kuner R, Behrens J, Offermans S (2002) Plexin B1 directly interacts
[20] with the PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 35:51–63.
[21] Caroline Moreau-Fauvarque, Atsushi Kumanogoh,Emeline Camand, Céline Jaillard,Gilles Barbin, Isabelle Boquet,The Transmembrane Semaphorin Sema4D/CD100, an Inhibitor of Axonal Growth, Is Expressed on Oligodendrocytes and Upregulated after CNS Lesion .The Journal of Neuroscience, October 8, 2003, 23(27):9229-9239
[22] Fawcett JW, Asher RA. 1999. The glial scar and central nervous system repair. Brain tissue Res. Bull. 49:377–91
[23] Rudge JS, Silver J. 1990. Inhibition of neurite outgrowth on astroglial scars in vitro. J. Neurosci. 10:3594–603
[24] Neiderost BP, Zimmermann DR, Schwab ME, Bandtlow CE. 1999. Bovine CNS myelin contains neurite growth-inhibitory activity associated with chondroitin sulfate proteoglycans. J. Neurosci. 19:8979–89
[25] Brittis PA, Canning DR, Silver J. 1992. Chondroitin sulfate as a regulator of neuronal patterning in the retina. Science 255:733–36
[26] Dou CL, Levine JM. 1994. Inhibition of neurite outgrowth by the NG2 chondroitin sulfate proteoglycan. J. Neurosci. 14:7616–
[27] Dergham P, Ellezam B, Essagian C, Avedissian H, Lubell WD, McKerracher L. 2002. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22:6570–77
[28] Reindl M, Khantane S, Ehling R, et al. Serum and cerebrospinal fluid antibodies to Nogo-A in patients with multiple sclerosis and acute neurologic disorders. J Neuroimmunol 2003;145:139–47
[29] Karnezis T, Mandemakers W, McQualter JL, et al. The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nat Neurosci 2004;7:736–44
[2] McGee AW, Strittmatter SM. The Nogo-66 receptor: focusing myelin inhibition of axon regeneration [J].Trends Neurosci, 2003,26(4):193-8.
[3] GrandPre T,Nakamura F,Vartanian T,et al.Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein [J]. Nature,2000,409:341-346.
[4] Fournier AE,Grand PT,Strittmatter SM. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration [J]. Nature, 2001, 409(6818):341-346.
[5] Liu BP, Fournier A, GrandPre T, Strittmatter SM. Myelin-associated glycoprotein as a functional ligand for the Nogo receptor [J]. Science.2002,297:1190-1193.
[6] Domeniconi M,Cao I,Spencer T,et al. Myelin associated glycoprotein interacts with the Nogo receptor to neurite outgrowth [J]. Nature, 2002,35:283-290.
[7] Wang KC,Koprivica V,Kim JA,et al.Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand and that inhibits neurite outgrowth [J].Nature.2002,417:941-944.
[8] Wang KC,Kim J, Srivasankaran R,et al.P75 interacts with the Nogo receptor as a co-receptor for Nogo,MAG and OMgp [J].Nature.2002,420:74-78.
[9] Wong K,Ren XR,Huang YZ, et al.Sinal transduction in neuronal migration: GTPase activating proteins and the small GTPase Cdc42 in the Slit- Robo pathway [J].Cell,2001,107:209-221.
[10] Hata Katsuhiko, Fujitani Masashi, RGMa inhibition promotes axonal growth and recovery after spinal cord injury[J]. Cell Biology. 173(2006): 47-58
[11] Schwab, J.M., Conrad, S., Monnier, P.P., Julien, S., Mueller, B.K. & Schluesener, H.J., Spinal cord injury induces lesional expression pattern of the repulsive guidance molecule (RGM) [J]. Neurosci. 21(2005) 1569-1576.
[12] Fawcett, J.W. & Asher, R.A. (1999) The glial scar and central nervousrepair.Brain Res. Bull., 49, 377–391.
[13] Schwab,M.E.&Bartholdi,D.(1996) Degeneration and regeneration of axons in the lesioned spinal cord. Physiol.Rev., 76,319¨C37
[14] Philippe P.Monnler,Ana Slerra, Friedrich Bonhoeffer,et al.RGM is a repulsive guidance molecule for retinal axons[J].Nature 2002,26(419):392-395
[15] Oldekamp J, Kramer N,et al. Expression pattern of the repulsive guidance molecules RGM A, B and C during mouse development. Gene Expr Patterns. 2004,4(3):283-288
[16] Yamaguchi Y,Katoh H,Yasui H,et al. RhoA inhibits the nerve growth factor-induced Racl activation through Rho-associated kinase-dependent pathway[J].J Biol Chem,2001,276 (22):18977-l8983
[17] Sabine Conrad, Harald Genth,et al.Neogenin-RGMa Signaling at the Growth Cone Is BMP-Independent and Involves RhoA, Rock and PKC[J]. J Biol Chem. 2008: 29(1):105-113
[18]袁宝玉,秦新月,彭国光,PPAR-γ激动剂对急性EAE大鼠脑白质TNF-αmRNA表达的影响[J]。重庆医科大学学报,2007 32(1)。
[1] Schwab ME, Bartholdi D (1996) Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 76:319–370.
[2] Bray GM, Villegas-Perez MP, Vidal-Sanz M,Aguayo AJ (1987) The use of peripheral nerve grafts to enhance neuronal survival, promote growth and permit terminal reconnections in the central nervous system of adult rats. J Exp Biol 132:5–19.
[3] Horner PJ, Gage FH (2000) Regenerating the damaged central nervous system.Nature 407:963–970.
[4] Fournier AE , GrandPre T , Strittmatter SM. [J]. Nature , 2001 , 409(6818):341-346.
[5] Wang KC,Kim JA,Sivasankaran R,et al. [J]. Nature,2002,420(6911):74-77.
[6] Tang S, Woodhall RW, Shen YJ, DeBellard ME, Saffel JL, et al. 1997b. Soluble myelinassociated glycoprotein found in vivo inhibits axonal regeneration. Mol. Cell. Neurosci. 9:333–46
[7] Liu BP, Fournier A, GrandPr′e T, Strittmatter SM. 2002. Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297:1190–93
[8] Wang KC, Koprivica V, Kim JA, Srivasankaran R, Guo Y, et al. 2002a. Oligodendrocytemyelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:941–44
[9] Mikol DD, Gulcher JR, Stefansson K. 1990. The oligodendrocyte-myelin glycoprotein belongs to a distinct family of proteins and contains the HNK-1 carbohydrate. J. Cell Biol. 110:471–79
[10] Wang KC,Kim JA,Sivasankaran R,et al. [J]. Nature,2002,420(6911):74-77.
[11] Schnell L, Schwab ME. 1990. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343:269–72
[12] Bareyre FM, Haudenschild B, Schwab ME. Long-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord. J Neurosci 2002;22:7097–110
[13] GrandPre′T, Li S, Strittmatter SM. Nogo-66 receptor antagonist peptide a) promotes axonal regeneration. Nature 2002;417:547–51
[14] Philippe P.Monnler,Ana Slerra, Friedrich Bonhoeffer,et al.RGM is a repulsive guidance molecule for retinal axons.Nature 2002,26(419):392-395
[15] Oldekamp J, Kramer N,et al. Expression pattern of the repulsive guidance molecules RGM A, B and C during mouse development. Gene Expr Patterns. 2004,4(3):283-288
[16] Eiji Matsunaga,ServaneTauszig-Delamasure,et al.RGM and its receptor neogenin regulate neuronal survival.Nature Cell biology. 2004, 6(8):749- 755
[17] Toshihide Yamashita, Bernhard K Mueller,Katsuhiko Hata,et al. Neogenin and repulsive guidance molecule signaling in the central nervous system. Neurobiology, 2007,17 (1):29-34
[18] Schwab JM, Conrad S,et al.Spinal cord injury-induced lesional expression of the repulsive guidance molecule (RGM). Eur J Neurosci. 2005,21(6):1569-1576
[19] Swiercz J, Kuner R, Behrens J, Offermans S (2002) Plexin B1 directly interacts
[20] with the PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 35:51–63.
[21] Caroline Moreau-Fauvarque, Atsushi Kumanogoh,Emeline Camand, Céline Jaillard,Gilles Barbin, Isabelle Boquet,The Transmembrane Semaphorin Sema4D/CD100, an Inhibitor of Axonal Growth, Is Expressed on Oligodendrocytes and Upregulated after CNS Lesion .The Journal of Neuroscience, October 8, 2003, 23(27):9229-9239
[22] Fawcett JW, Asher RA. 1999. The glial scar and central nervous system repair. Brain tissue Res. Bull. 49:377–91
[23] Rudge JS, Silver J. 1990. Inhibition of neurite outgrowth on astroglial scars in vitro. J. Neurosci. 10:3594–603
[24] Neiderost BP, Zimmermann DR, Schwab ME, Bandtlow CE. 1999. Bovine CNS myelin contains neurite growth-inhibitory activity associated with chondroitin sulfate proteoglycans. J. Neurosci. 19:8979–89
[25] Brittis PA, Canning DR, Silver J. 1992. Chondroitin sulfate as a regulator of neuronal patterning in the retina. Science 255:733–36
[26] Dou CL, Levine JM. 1994. Inhibition of neurite outgrowth by the NG2 chondroitin sulfate proteoglycan. J. Neurosci. 14:7616–
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