sTNFRⅠ对EAN治疗作用的免疫学和组织病理学研究
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摘要
格林—巴利综合征(Guillain–Barre′Syndrome,GBS),是由免疫介导产生的急性周围神经疾病。在世界各地发病分布广泛,在我国发病率较高,是威害人们健康的常见疾病之一,实验性自身免疫性神经炎(experimental autoimmune neuritis,EAN)是一类由T细胞介导的周围神经系统自身免疫性疾病,其临床表现、免疫学发病机制、神经电生理及病理学改变诸多方面与人类GBS非常相似,是目前常用的研究GBS发病机制和治疗的动物模型。
为进一步研究GBS发病机制和治疗,近年来国内外研究者对于诱导Lewis大鼠产生EAN的髓鞘周围的一些细胞因子以及神经生长因子作用的研究越来越多。已有研究表明可溶性肿瘤坏死因子1型受体(soluble tumor necrosis factor receptor type I,sTNFR I)在自身免疫性疾病中有着不可或缺的保护作用,它具有抑制肿瘤坏死因子(tumor necrosis factor, TNF)的活性、导致T细胞凋亡和清除淋巴细胞、抑制干扰素-γ(interferon-γ, FN-γ)的分泌,以及抑制炎性细胞的浸润等作用。
本项研究即通过给予P0 180-199(SSKRGRQTPVLYAMLDHSRS)多肽与完全弗氏佐剂(Complete Freund's adjuvant, CFA)的混合液免疫Lewis大鼠诱导产生EAN动物模型。实验组分为两组分别给予sTNFR I干预治疗和PBS干预治疗后,通过观察临床评分,炎细胞浸润,坐骨神经干脱髓鞘程度并进行组间对照比较表明:接受sTNFR I治疗的Lewis大鼠与磷酸盐缓冲液(phosphate buffed saline,PBS)治疗组相比临床评分较低,炎细胞浸润减少,且其坐骨神经干脱髓鞘程度轻。本研究通过评价sTNFR I对EAN的治疗效果,期望为GBS的临床治疗提供新的思路与策略。
目的: 1.研究P0 180-199多肽诱导建立EAN动物模型的可能性,为GBS的基础研究提供良好实用的动物模型。
2.探讨sTNFR I对EAN临床症状及免疫功能相关的细胞如:巨噬细胞、CD4 +和CD8 + T细胞的影响。
3.探讨sTNFR I对EAN成模鼠的TNF-α、IL-4影响,研究细胞因子在其发病机制中的作用。为进一步探讨sTNFR I治疗EAN提供理论依据。方法:用P0 180-199多肽与弗氏完全佐剂的混合液充分乳化后多点皮下注入6-8周龄SPF级雌性Lewis鼠,建立EAN动物模型。将30只健康、成年、雌性SPF级Lewis大鼠随机分为正常对照组、sTNFR I治疗EAN组、PBS治疗EAN组。对照组同期注入等量的PBS。观察实验鼠临床症状,并进行临床评分;通过苏木精-伊红(HE)染色观察淋巴细胞、巨噬细胞的浸润情况及固绿髓鞘染色法观察髓鞘脱失程度来确定EAN是否成模。免疫后第10天给予sTNFR I或PBS腹腔内注射,分别在治疗后对各组大鼠进行组织病理学和免疫学指标检测。
结果:
1. EAN组中77%Lewis鼠临床评分在1.5分以上,经病理学观察髓鞘脱失情况证实了实验动物EAN成模。
2.接受sTNFR I治疗的Lewis大鼠与PBS治疗组相比临床评分较低,坐骨神经病理显示炎细胞浸润减少,且其坐骨神经干脱髓鞘程度轻。
3.接受sTNFR I治疗的Lewis大鼠与PBS治疗组相比坐骨神经组织中巨噬细胞、CD4 +和CD8 + T细胞的浸润显著减少( P < 0. 01);TNF-α分泌减少,IL-4的分泌增多( P < 0. 01)。
4.免疫后18d PBS治疗组与sTNFR I治疗组比较,血清中TNF-α的水平有统计学意义,差异有显著性(P < 0. 01)。
结论:用人工合成P0 180-199多肽免疫Lewis鼠可成功诱导EAN模型,成模率约77%。该实验动物模型为GBS的基础研究奠定了基础。
2.sTNFR I通过减轻其免疫炎性级联反应而达到治疗EAN作用。
Guillain–Barre′Syndrome (GBS) is an acute immune-mediated perioheral nervous system diseases. It has been distributed all over the world, it has a high morbidity in our country. Experimental autoimmune neuritis (EAN) is a T- cell-mediated, inflammatory demyelinating disease of peripheral nervous system(PNS) that serves as a model for GBS in humans. It has histopathological, electrophysiological and clinical similarities to the GBS and therefore is used as an animal model to understand the pathogenesis of GBS.
In recent years there have been a number of studies examining the kinetics and function of cytokines, and other growth factors during the course of myelin induced EAN in the Lewis rat. Many observations show that neutralization of TNF with sTNFR I can inhibit the development of EAN and confirm that TNF plays a prominent role in autoimmune diseases. The principal ameliorative effects of sTNFR I therapy would be to neutralize TNF activity, thereby reducing TNF mediated pathology. Depression of T-cell proliferation and IFN-γsecretion, as well as decreased local lymphocytic traffic resulting from sTNFR I neutralization of TNF, probably play an essential role in this protection. In our study, we investigated the effects of soluble TNFR type I (sTNFR I) in EAN induced in mice by P0 peptide 180–199 and Freund’s complete adjuvant. Our data from two different therapeutic regimens indicate that the administration of sTNFR I effectively ameliorated the clinical and pathological signs of EAN, i.e., decreased its severity, shortened its duration, and reduced inflammatory cell infiltration into the peripheral nervous system. These data emphasize a central role of TNF during the process of EAN and also indicate beneficial effects of soluble TNF receptors in the treatment of EAN. These data directly demonstrate a pivotal role for TNF in the development of EAN and also suggest that sTNFR I may have therapeutic potential for alleviating GBS in humans.
Objective:
1. To study probability of in experimental autoimmune neuritis with P0 180-199 peptide induced and provide a good and available animal models for basic researches of GBS.
2. To elucidate the effect of sTNFR I on EAN by it’s symptoms and macrophages, or CD4 + or CD8 + T cells.
3. To elucidate the effect of sTNFR I on EAN by it’s secretion of TNF-αand production of IL-4
Methods:
EAN animal model was established by immunizing female Lewis rats (6-8 weeks) with P0 180-199 peptide and completed Freund’s adjuvant ( CFA ). A total of 30 healthy adult female Lewis rats were randomly divided into control group, sTNFR I treated group and PBS (phosphate buffered saline) treated group. EAN model Lewis were determined by measurement clinical score and Infiltration of lymphocytes and macrophages in sciatic nerves sections and demyelination in sciatic nerves of Lewis rats The animals were given sTNFR I or PBS intraperitoneally. Then histopathological and immunological methods were used after treatment , respectively, to detect the effect of sTNFR I on EAN.
Results:
Signs of EAN occurred in 77% of Lewis rats in the EAN group ,which was confirmed by the clinical score>1.5 grade and the demyelination in sciatic nerves of Lewis rats. Compared with PBS treated group, sTNFR I treated group displayed less severe clinical sign, decreased infiltration of inflammatory cells into sciatic nerves,milder demyelination, decreased infiltration of macrophages, or CD4 + or CD8 + T cells into sciatic nerves , reduced secretion of TNF-αand increased production of IL-4 .
Conclusions:
1. Immunization with the P0 180-199 peptide can induce EAN in Lewis rats .The achievement ratio of EAN model was 77% . This animal models builds a base for basic researches of GBS.
2.sTNFR I plays an important role in amelioration of EAN.
为进一步研究GBS发病机制和治疗,近年来国内外研究者对于诱导Lewis大鼠产生EAN的髓鞘周围的一些细胞因子以及神经生长因子作用的研究越来越多。已有研究表明可溶性肿瘤坏死因子1型受体(soluble tumor necrosis factor receptor type I,sTNFR I)在自身免疫性疾病中有着不可或缺的保护作用,它具有抑制肿瘤坏死因子(tumor necrosis factor, TNF)的活性、导致T细胞凋亡和清除淋巴细胞、抑制干扰素-γ(interferon-γ, FN-γ)的分泌,以及抑制炎性细胞的浸润等作用。
本项研究即通过给予P0 180-199(SSKRGRQTPVLYAMLDHSRS)多肽与完全弗氏佐剂(Complete Freund's adjuvant, CFA)的混合液免疫Lewis大鼠诱导产生EAN动物模型。实验组分为两组分别给予sTNFR I干预治疗和PBS干预治疗后,通过观察临床评分,炎细胞浸润,坐骨神经干脱髓鞘程度并进行组间对照比较表明:接受sTNFR I治疗的Lewis大鼠与磷酸盐缓冲液(phosphate buffed saline,PBS)治疗组相比临床评分较低,炎细胞浸润减少,且其坐骨神经干脱髓鞘程度轻。本研究通过评价sTNFR I对EAN的治疗效果,期望为GBS的临床治疗提供新的思路与策略。
目的: 1.研究P0 180-199多肽诱导建立EAN动物模型的可能性,为GBS的基础研究提供良好实用的动物模型。
2.探讨sTNFR I对EAN临床症状及免疫功能相关的细胞如:巨噬细胞、CD4 +和CD8 + T细胞的影响。
3.探讨sTNFR I对EAN成模鼠的TNF-α、IL-4影响,研究细胞因子在其发病机制中的作用。为进一步探讨sTNFR I治疗EAN提供理论依据。方法:用P0 180-199多肽与弗氏完全佐剂的混合液充分乳化后多点皮下注入6-8周龄SPF级雌性Lewis鼠,建立EAN动物模型。将30只健康、成年、雌性SPF级Lewis大鼠随机分为正常对照组、sTNFR I治疗EAN组、PBS治疗EAN组。对照组同期注入等量的PBS。观察实验鼠临床症状,并进行临床评分;通过苏木精-伊红(HE)染色观察淋巴细胞、巨噬细胞的浸润情况及固绿髓鞘染色法观察髓鞘脱失程度来确定EAN是否成模。免疫后第10天给予sTNFR I或PBS腹腔内注射,分别在治疗后对各组大鼠进行组织病理学和免疫学指标检测。
结果:
1. EAN组中77%Lewis鼠临床评分在1.5分以上,经病理学观察髓鞘脱失情况证实了实验动物EAN成模。
2.接受sTNFR I治疗的Lewis大鼠与PBS治疗组相比临床评分较低,坐骨神经病理显示炎细胞浸润减少,且其坐骨神经干脱髓鞘程度轻。
3.接受sTNFR I治疗的Lewis大鼠与PBS治疗组相比坐骨神经组织中巨噬细胞、CD4 +和CD8 + T细胞的浸润显著减少( P < 0. 01);TNF-α分泌减少,IL-4的分泌增多( P < 0. 01)。
4.免疫后18d PBS治疗组与sTNFR I治疗组比较,血清中TNF-α的水平有统计学意义,差异有显著性(P < 0. 01)。
结论:用人工合成P0 180-199多肽免疫Lewis鼠可成功诱导EAN模型,成模率约77%。该实验动物模型为GBS的基础研究奠定了基础。
2.sTNFR I通过减轻其免疫炎性级联反应而达到治疗EAN作用。
Guillain–Barre′Syndrome (GBS) is an acute immune-mediated perioheral nervous system diseases. It has been distributed all over the world, it has a high morbidity in our country. Experimental autoimmune neuritis (EAN) is a T- cell-mediated, inflammatory demyelinating disease of peripheral nervous system(PNS) that serves as a model for GBS in humans. It has histopathological, electrophysiological and clinical similarities to the GBS and therefore is used as an animal model to understand the pathogenesis of GBS.
In recent years there have been a number of studies examining the kinetics and function of cytokines, and other growth factors during the course of myelin induced EAN in the Lewis rat. Many observations show that neutralization of TNF with sTNFR I can inhibit the development of EAN and confirm that TNF plays a prominent role in autoimmune diseases. The principal ameliorative effects of sTNFR I therapy would be to neutralize TNF activity, thereby reducing TNF mediated pathology. Depression of T-cell proliferation and IFN-γsecretion, as well as decreased local lymphocytic traffic resulting from sTNFR I neutralization of TNF, probably play an essential role in this protection. In our study, we investigated the effects of soluble TNFR type I (sTNFR I) in EAN induced in mice by P0 peptide 180–199 and Freund’s complete adjuvant. Our data from two different therapeutic regimens indicate that the administration of sTNFR I effectively ameliorated the clinical and pathological signs of EAN, i.e., decreased its severity, shortened its duration, and reduced inflammatory cell infiltration into the peripheral nervous system. These data emphasize a central role of TNF during the process of EAN and also indicate beneficial effects of soluble TNF receptors in the treatment of EAN. These data directly demonstrate a pivotal role for TNF in the development of EAN and also suggest that sTNFR I may have therapeutic potential for alleviating GBS in humans.
Objective:
1. To study probability of in experimental autoimmune neuritis with P0 180-199 peptide induced and provide a good and available animal models for basic researches of GBS.
2. To elucidate the effect of sTNFR I on EAN by it’s symptoms and macrophages, or CD4 + or CD8 + T cells.
3. To elucidate the effect of sTNFR I on EAN by it’s secretion of TNF-αand production of IL-4
Methods:
EAN animal model was established by immunizing female Lewis rats (6-8 weeks) with P0 180-199 peptide and completed Freund’s adjuvant ( CFA ). A total of 30 healthy adult female Lewis rats were randomly divided into control group, sTNFR I treated group and PBS (phosphate buffered saline) treated group. EAN model Lewis were determined by measurement clinical score and Infiltration of lymphocytes and macrophages in sciatic nerves sections and demyelination in sciatic nerves of Lewis rats The animals were given sTNFR I or PBS intraperitoneally. Then histopathological and immunological methods were used after treatment , respectively, to detect the effect of sTNFR I on EAN.
Results:
Signs of EAN occurred in 77% of Lewis rats in the EAN group ,which was confirmed by the clinical score>1.5 grade and the demyelination in sciatic nerves of Lewis rats. Compared with PBS treated group, sTNFR I treated group displayed less severe clinical sign, decreased infiltration of inflammatory cells into sciatic nerves,milder demyelination, decreased infiltration of macrophages, or CD4 + or CD8 + T cells into sciatic nerves , reduced secretion of TNF-αand increased production of IL-4 .
Conclusions:
1. Immunization with the P0 180-199 peptide can induce EAN in Lewis rats .The achievement ratio of EAN model was 77% . This animal models builds a base for basic researches of GBS.
2.sTNFR I plays an important role in amelioration of EAN.
引文
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[9] Finger JH, Bronson RT, Harris B et al. The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons[J]. J Neurosci ,2002,22(23): 10346-56.
[10] Barallobre MJ, Pascual M, Del Rio JA et al. The Netrin family of guidance factors: emphasis on Netrin-1 signalling[J]. Brain Res Brain Res Rev,2005, 49(1): 22-47.
[11] Madison RD, Zomorodi A, Robinson GA . Netrin-1 and peripheral nerve regeneration in the adult rat[J]. Exp Neuro,161(2): 563-70.
[12] Manitt C, Wang D, Kennedy TE et al. Positioned to inhibit: Netrin-1 and netrin receptor expression after spinal cord injury[J]. J Neurosci Res,2006, 84(8): 1808-20.
[13] Moon C, Kim H, Ahn M et al. Enhanced expression of netrin-1 protein in the sciatic nerves of Lewis rats with experimental autoimmune neuritis: possible role of the netrin-1/DCC binding pathway in an autoimmune PNS disorder[J]. J Neuroimmunol .2006,172(1-2): 66-72.
[14] Jarjour AA, Manitt C, Moore SW et al. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord[J]. J Neurosci 2003,23(9): 3735-44.
[15] Guijarro P, Simo S, Pascual M et al. Netrin1 exerts a chemorepulsive effect on migrating cerebellar interneurons in a Dcc-independent way[J]. Mol Cell Neurosci ,2006,33(4): 389-400.
[16] Kim TH, Lee HK, Seo IA et al. Netrin induces down-regulation of its receptor, Deleted in Colorectal Cancer, through the ubiquitin-proteasome pathway in the embryonic cortical neuron[J]. J Neurochem ,2005, 95(1): 1-8.
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[21]. Liu Y, Stein E, Oliver T et al. Novel role for netrins in regulating epithelial behavior during lung branching morphogenesis[J]. Curr Biol ,2004, 14(10):897-905.
[22]. Yebra M, Montgomery AM, Diaferia GR et al. Recognition of the neural chemoattractant Netrin-1 by integrins a6b4and a3b1 regulates epithelial cell adhesion and migration[J]. Dev Cell ,2003, 5(5):695-707.
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[1]. Manitt C, Kennedy T E. Where the rubber meets the road: netrin expression and function in developing and adult nervous systems[J]. Prog Brain Res 2002, 137:425-42.
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[8]余科科,汪思应,张成岗.神经突起生长导向因子(netrin)受体家族研究进展[J].中国神经科学杂志2004 ,20: 476-80.
[9] Finger JH, Bronson RT, Harris B et al. The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons[J]. J Neurosci ,2002,22(23): 10346-56.
[10] Barallobre MJ, Pascual M, Del Rio JA et al. The Netrin family of guidance factors: emphasis on Netrin-1 signalling[J]. Brain Res Brain Res Rev,2005, 49(1): 22-47.
[11] Madison RD, Zomorodi A, Robinson GA . Netrin-1 and peripheral nerve regeneration in the adult rat[J]. Exp Neuro,161(2): 563-70.
[12] Manitt C, Wang D, Kennedy TE et al. Positioned to inhibit: Netrin-1 and netrin receptor expression after spinal cord injury[J]. J Neurosci Res,2006, 84(8): 1808-20.
[13] Moon C, Kim H, Ahn M et al. Enhanced expression of netrin-1 protein in the sciatic nerves of Lewis rats with experimental autoimmune neuritis: possible role of the netrin-1/DCC binding pathway in an autoimmune PNS disorder[J]. J Neuroimmunol .2006,172(1-2): 66-72.
[14] Jarjour AA, Manitt C, Moore SW et al. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord[J]. J Neurosci 2003,23(9): 3735-44.
[15] Guijarro P, Simo S, Pascual M et al. Netrin1 exerts a chemorepulsive effect on migrating cerebellar interneurons in a Dcc-independent way[J]. Mol Cell Neurosci ,2006,33(4): 389-400.
[16] Kim TH, Lee HK, Seo IA et al. Netrin induces down-regulation of its receptor, Deleted in Colorectal Cancer, through the ubiquitin-proteasome pathway in the embryonic cortical neuron[J]. J Neurochem ,2005, 95(1): 1-8.
[17] Ahn KJ, Seo IA, Lee HK et al. Down-regulation of UNC5 homologue expression after the spinal cord injury in the adult rat[J]. Neurosci Lett,2007, 419(1):43-8.
[18] Hong K, Hinck L, Nishiyama M et al. A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion[J]. Cell,1999, 97(7): 927-41.
[19]. Srinivasan K, Strickland P, Valdes A et al. Netrin-1/neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland morphogenesis[J]. Dev Cell 2003, 4(3):371-82.
[20]. Strickland P, Shin GC, Plump A et al. Slit2 and netrin 1 act synergistically as adhesive cues to generate tubular bi-layers during ductal morphogenesis[J]. Development ,2006, 133(5):823-32.
[21]. Liu Y, Stein E, Oliver T et al. Novel role for netrins in regulating epithelial behavior during lung branching morphogenesis[J]. Curr Biol ,2004, 14(10):897-905.
[22]. Yebra M, Montgomery AM, Diaferia GR et al. Recognition of the neural chemoattractant Netrin-1 by integrins a6b4and a3b1 regulates epithelial cell adhesion and migration[J]. Dev Cell ,2003, 5(5):695-707.
[23]. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion[J]. Cell, 1992, 69(1):11-25.
[24]. Serafini T, Kennedy TE, Galko MJ et al. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6[J]. Cell, 1994, 78(3):409-24.
[25]. Koch M, Murrell JR, Hunter DD et al.A novel member of the netrin family, beta-netrin, shares homology with the beta chain of laminin: identification, expression, and functional characterization[J]. J Cell Biol ,2000, 151(2):221-34.
[26]. Carmeliet P, Tessier-Lavigne M.Common mechanisms of nerve and blood vessel wiring[J]. Nature ,2005, 436(7048):193-200.
[27]. Lu X, Le Noble F, Yuan L et al.The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system[J]. Nature,2004,432(7014):179-86.
[28]. Park KW, Crouse D, Lee M et al.The axonal attractant Netrin-1 is an angiogenic factor[J]. Proc Natl Acad Sci USA ,2004, 101(46):16210-15.
[29]. Nguyen A, Cai H.Netrin-1 induces angiogenesis via a DCC-dependent ERK1/2-eNOS feed-forward mechanism[J]. Proc Natl Acad Sci USA,2006, 103(17):6530-35.
[30]. Manitt C, Colicos MA, Thompson KM et al.Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord[J]. J Neurosci ,2001, 21(11):3911-22.
[31]. Shekarabi M, Moore SW, Tritsch NX et al. Deleted in colorectal cancer binding netrin-1 mediates cell substrate adhesion and recruits Cdc42, Rac1, Pak1, and N-WASP into an intracellular signaling complex that promotes growth cone expansion[J]. J Neurosci, 2005, 25(12):3132-41.
[32]. Salzer JL.Polarized domains of myelinated axons[J]. Neuron, 2003, 40(2):297-318.
[33]. Poliak S, Peles E. The local differentiation of myelinated axons at nodes of Ranvier[J]. Nat Rev Neurosci ,2003, 4(12):968-80.
[34]. Shekarabi M, Kennedy TE.The netrin-1 receptor DCC promotes filopodia formation and cell spreading by activating Cdc42 and Rac1[J]. Mol Cell Neurosci,2002, 19(1):1-17.
[35]. Barallobre MJ, Pascual M, Del Rio JA et al.The netrin family of guidance factors: emphasis on netrin-1 signalling[J]. Brain Res Brain Res Rev, 2005, 49(1):22-47.
[36]. Li W, Lee J, Vikis HG et al.Activation of FAK and Src are receptor-proximal events required for netrin signaling[J]. Nat Neurosci ,2004, 7(11):1213-21.
[37]. Liu G, Beggs H, Jurgensen C et al. Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction[J]. Nat Neurosci, 2004, 7(11):1222-32.
[38]. Wozniak MA, Modzelewska K, Kwong L et al.Focal adhesion regulation of cell behavior[J]. Biochim Biophys Acta ,2004, 1692(2-3):103-19.
[39]. Forsthoefel DJ, Liebl EC, Kolodziej PA et al.The Abelson tyrosine kinase, the Trio GEF and Enabled interact with the Netrin receptor Frazzled in Drosophila[J]. Development, 2005, 132(8):1983-94.
[40]. Li W, Aurandt J, Jurgense C et al.FAK and Src kinases are required for netrin-induced tyrosine phosphorylation of UNC5[J]. J Cell Sci 2006, 119(pt1):47-55.
[41]. Sieg DJ, Hauck CR, Schlaepfer DD.Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration[J]. J Cell Sci ,1999, 112(pt16):2677-91.
[42]. Fearon ER, Cho KR, Nigro JM et al. Identification of a chromosome 18q gene that is altered in colorectal cancers[J]. Science ,1990, 247(4983):49-56.
[43]. Mehlen P, Mazelin L. The dependence receptors DCC and UNC5H as a link between neuronal guidance and survival[J]. Biol Cell, 2003, 95(7):425-36.
[44]. Tsai HH, Macklin WB, Miller RH. Netrin-1 is required for the normal development of spinal cord oligodendrocytes[J]. J Neurosci ,2006, 26(7):1913-22.