Nogo氨基末端在视神经再生中的作用及机制研究
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摘要
眼睛把光投射到视网膜感受器并转化成电信号冲动，通过视神经传递到脑部而形成视觉。视网膜神经节细胞（retina ganglion cells, RGCs）的轴突形成视神经，而视神经损伤是视力丧失的原因之一。虽然视神经损伤在视力丧失中仅占一小部分比例，但其造成的视力损害是不可逆的。研究表明视神经受损后无法再生，其主要原因是视网膜神经节细胞损伤后轴突缺乏再生能力以及视网膜神经节细胞逆行退化导致节细胞凋亡。在成年哺乳动物中枢神经轴突再生失败已被证实主要是由于存在内源性抑制剂抑制轴突再生，这些抑制剂包括Nogo A、髓鞘相关性糖蛋白（Myelin associatedglycoprotein, MAG）和少突胶质细胞髓鞘糖蛋白（Oligodendrocyte myelin glycoprotein,OMGP）等。在这些内源性的抑制剂当中，Nogo A一直备受关注。Nogo A是髓磷脂来源的抑制剂，包括两个功能结构域：Nogo66和Nogo氨基末端结构域。不同的结构域可与不同的受体结合发挥不完全相同的生物学功能，Nogo66与其受体（Nogo66receptor, NgR）结合发挥双重作用，既抑制轴突再生，又在中枢神经系统神经发生过程中调节轴突生长、导向和塑形，而Nogo氨基末端只发挥抑制作用。Nogo氨基末端是否能够抑制视神经再生及其作用机制尚未见报道。
整合素是一种细胞表面糖蛋白，由非共价键连接的α和β两个亚单位形成异二聚体复合物。整合素衔接细胞外基质的配体，形成粘附复合物，为肌动蛋白细胞骨架提供耦合，这对细胞的扩展、促进生长锥向远端的生长都是必须的。Nogo氨基末端通过整合素抑制细胞粘附和轴突生长。整合素αv和整合素α5广泛分布在中枢神经系统，Nogo氨基末端是否通过整合素αv和（或）整合素α5信号通路在视神经轴突生长过程中发挥作用仍需进一步研究。
本课题主要进行了以下三个方面的研究：1、观察Nogo氨基末端信号通路在视觉神经系统中的表达情况。2、证实Nogo氨基末端对于视神经再生修复具有抑制作用。3、证实Nogo氨基末端通过整合素αv信号通路，而不是α5信号通路发挥抑制作用。
目的:证实Nogo氨基末端对于视神经再生具有抑制效应且其通过整合素信号通路发挥作用，为治疗视神经损伤提供新的策略，同时也为中枢神经损伤修复研究提供借鉴和参考。
方法：采用免疫组织化学方法检测整合素αv、整合素α5和成簇黏附激酶（focaladhesion kinase, FAK）蛋白的表达，体外筛选针对大鼠Nogo A的小分子干扰RNA序列，重组腺相关病毒包转和纯化。原代培养视网膜神经节细胞转染rAAV2/8NC siRNA，rAAV2/8Nogo A siRNA，Nogo66竞争拮抗剂（Nep140）和Nogo氨基末端功能片段（△20）刺激，Thy1免疫荧光染色观察视网膜神经节细胞轴突长度。建立视神经钳夹伤模型，玻璃体腔注射PBS，rAAV2/8NC siRNA，rAAV2/8Nogo A siRNA，Nep140和△20，荧光金逆行标记视网膜神经节细胞存活率，GAP43染色观察再生视神经纤维情况，F VEP检测视神经功能。Western Blot检测整合素αv、整合素α5和FAK蛋白的表达。RhoA G LISA法检测RhoA活性。
主要结果和结论如下：
1、免疫组织化学染色方法证实整合素αv、整合素α5以及整合素的下游关键分子FAK均可在大鼠的视皮质、视网膜以及视神经中表达。这些Nogo氨基末端信号通路关键分子表达在视觉通路上，说明Nogo氨基末端有可能通过整合素信号途径发挥作用。
2、Nogo A靶向siRNA可高效特异的下调RGCs的Nogo A的表达，而通用阴性对照序列对Nogo A的表达无影响，成功筛选出有效RNAi序列，为本研究中构建Nogo A靶向siRNA重组腺相关病毒表达载体提供了实验前提。Nogo A靶向siRNA重组腺相关病毒表达载体可有效的抑制原代培养的RGCs以及活体动物视网膜神经节细胞层的Nogo A蛋白的表达，且在动物体内Nogo A的抑制效应于病毒注射后4w即已存在，8w时仍持续，提示重组腺相关病毒已成功的整合到RGCs基因组中，从而可以发挥其长久RNA干扰作用。
3、体外实验采用RNAi完全抑制Nogo A和针对Nogo A的部分片段（Nogo66）的拮抗剂（Nep140）均可促进RGCs轴突生长，但完全抑制Nogo A后促生长作用更强，说明Nogo A上尚存在除Nogo66外的抑制片段，而给予Nogo氨基末端的功能片段△20能够明显抑制RGCs轴突生长，证实Nogo氨基末端即为Nogo A上除Nogo66外的抑制片段。
4、在体动物实验，荧光金逆行标记观察RGCs存活率，发现Nogo氨基末端对RGCs存活的抑制作用，通过生长相关蛋白43（growth associatted protein43, GAP43）免疫荧光组织化学染色观察视神经钳夹伤后视神经再生情况证实Nogo氨基末端抑制神经再生修复；F VEP检测证明Nogo氨基末端不利于视神经功能的恢复，提示Nogo氨基末端抑制视神经再生修复及功能恢复。
5、通过调控Nogo A氨基末端功能片段观察其下游信号通路蛋白整合素αv、整合素α5、FAK和RhoA的表达变化，发现Nogo氨基末端通过整合素αv信号通路发挥抑制作用。
Eyes are organs detecting light and converting it into electro chemical impulses inretina. Retinal ganglion cells (RGCs) axons form the optic nerve (ON), injury of which hasbeen one of the causes of visual loss. Although ON injury accounts for only smallproportion of visual loss, the impaired vision is in general not recoverable. After injury, ONis unable to regenerate, which mainly because that RGCs retrogradely degenerate followinginjury and lack the ability of regenerating axons. Studies showed that the failure of axonsregeneration in adult mammalian central nervous system was partly due to the presence ofendogenous inhibitors of axon regeneration, which include Nogo A, myelin associatedglycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMGP). Among thoseendogenous inhibitors, Nogo A has received much attention. Nogo A is a myelin associatedinhibitor, the function of which depends on its two inhibitory domains:66amino aciddomain (Nogo66) and N terminal domain (Amino Nogo). The Nogo66domain bothinhibits axonal regeneration and regulates axonal growth, guidance and CNS plasticityneurogenesis. Conversely, Amino Nogo only exerts an inhibitory effect. However, the roleand the mechanism of Amino Nogo in the optic nerve have not been fully elucidated.
Integrins are heterodimeric cell surface glycoproteins composed of α and β subunitsthat are non covalently connected. Integrins bind ligands in the extracellular matrix andform adhesion complexes that couple to the actin cytoskeleton. These complexes arenecessary for cellular expansion and axonal growth. Amino Nogo inhibits cell adhesion andaxonal outgrowth by inhibiting integrins, and the effect of Amino Nogo is related todifferent integrin subunits in axonal outgrowth. Integrins αv and α5, are widely expressedin the CNS, however, which integrin subunit is the main player in the Amino Nogo–integrinsignaling pathway operating in axonal outgrowth remains unknown.
The study is divided into three parts:1、Investigating the proteins of Amino Nogosignalling pathway expression in the optic nerve system.2、Investigating the inhibitoryeffect of Amino Nogo on optic nerve regeneration.3、Investigating the Amino Nogo inhibiting RGC axonal outgrowth primarily through the integrin αv signaling pathway, butnot integrin α5signaling pathway.
Aim: To regulat the Amino Nogo to confirm that the Amino Nogo inhibits nerveregeneration. To investigate the mechanism of Amino Nogo inhibiting optic nerveregeneration. To provide a new strategy for the treatment of optic nerve damage, as well asto provide reference for central nervous system injury repair research.
Methods: In this study we detected the expression of integrin αv, integrin α5andfocal adhesion kinase (FAK) by immunohistochemistry. Screening for siRNA sequencetargeting rat Nogo A mRNA in vitro. Production and purification of RecombinantAdenoassociated VirusVectors (rAAV). rAAV2/8NC siRNA, rAAV2/8Nogo A siRNA, apeptide antagonist of Nogo66of Nogo A (Nep140), and a recombinant rat Nogo A Fcchimeric protein (△20) were added in the primary RGCs. The axonal length of RGCs wasassayed by Thy1immunofluorescence stained. We injected PBS, rAAV2/8NC siRNA,rAAV2/8Nogo A siRNA, Nep140and△20in vitreous cavity of the SD rats following opticnerve crush injury and observed the RGCs survival rate by retrograde fluorogold labeling,the number of regenerating axons by GAP43immunofluorescence stained and the opticnerve function recovery by F VEP recording. Western Blot assayed the expression changesof integrin αv, integrin α5and FAK. RhoA activition was measured by RhoA G LISA.
The main results and conclusions are as follows:
1、Integrin αv, integrin α5and focal adhesion kinase (FAK) were widely expressed inthe visual cortex, retina and optic nerve by immunohistochemical staining. TheAmino Nogo–integrin signaling pathway related key proteins expressed in the visualsystem indicating that Amino Nogo plays a role may through the integrin signaling pathway.This study establishes the foundation for further experiments.
2、Our test showed the siRNA targeting to Nogo A could efficiently down regulatedNogo A expression in RGCs, but the control siRNA had no influence on the Nogo A level,which successfully screened effective RNAi sequence and laid the foundation forconstructing the recombinant virus vector. The recombinant virus vector could efficientlyinhibit the Nogo A protein of primary RGCs in vitro. In vivo, the inhibition has beenexisted4weeks after virus injection and maintained till8weeks in retinal ganglion celllayer, which confirmed it had been integrated into RGCs genome and might have longer inhibition
3、In vitro test showed Nogo66antagonist peptide (Nep1–40) promoted RGCsoutgrowth, which indicated Nogo66functional domains can inhibit the outgrowth of RGCs.In addition, Nogo siRNA also promoted axonal outgrowth of RGCs and the length of RGCsaxons were longer than Nep140group, which suggested that except Nogo66functionaldomains can inhibit axonal growth, its other functional domain, Amino Nogo domain, canalso inhibit the outgrowth of RGCs. The recombinant rat Nogo A Fc chimeric protein (△20)can significantly inhibit the RGCs outgrowth, further indicated that Amino Nogo played aninhibitory effect.
4、In vivo test showed Amino Nogo inhibited the survival rate of RGCs by fluoroGoldretrogradely labeled RGC neurons by injecting, and Amino Nogo inhibited nerveregeneration following the optic nerve injury by growth associatted protein43(GAP43)immunofluorescence staining. The F VEP recording also demonstrated that Amino Nogowas harmful to the recovery of optic nerve function. All of the above results suggest thatAmino Nogo inhibits optic nerve regeneration and functional recovery.
5、In vitro and in vivo experiments showed Amino Nogo inhibited optic nerveregeneration through the integrin αv signaling pathway by observing the expressionchanges of integrin αv, integrin α5, FAK and RhoA, which were Amino Nogo signalingpathway downstream proteins.
整合素是一种细胞表面糖蛋白，由非共价键连接的α和β两个亚单位形成异二聚体复合物。整合素衔接细胞外基质的配体，形成粘附复合物，为肌动蛋白细胞骨架提供耦合，这对细胞的扩展、促进生长锥向远端的生长都是必须的。Nogo氨基末端通过整合素抑制细胞粘附和轴突生长。整合素αv和整合素α5广泛分布在中枢神经系统，Nogo氨基末端是否通过整合素αv和（或）整合素α5信号通路在视神经轴突生长过程中发挥作用仍需进一步研究。
本课题主要进行了以下三个方面的研究：1、观察Nogo氨基末端信号通路在视觉神经系统中的表达情况。2、证实Nogo氨基末端对于视神经再生修复具有抑制作用。3、证实Nogo氨基末端通过整合素αv信号通路，而不是α5信号通路发挥抑制作用。
目的:证实Nogo氨基末端对于视神经再生具有抑制效应且其通过整合素信号通路发挥作用，为治疗视神经损伤提供新的策略，同时也为中枢神经损伤修复研究提供借鉴和参考。
方法：采用免疫组织化学方法检测整合素αv、整合素α5和成簇黏附激酶（focaladhesion kinase, FAK）蛋白的表达，体外筛选针对大鼠Nogo A的小分子干扰RNA序列，重组腺相关病毒包转和纯化。原代培养视网膜神经节细胞转染rAAV2/8NC siRNA，rAAV2/8Nogo A siRNA，Nogo66竞争拮抗剂（Nep140）和Nogo氨基末端功能片段（△20）刺激，Thy1免疫荧光染色观察视网膜神经节细胞轴突长度。建立视神经钳夹伤模型，玻璃体腔注射PBS，rAAV2/8NC siRNA，rAAV2/8Nogo A siRNA，Nep140和△20，荧光金逆行标记视网膜神经节细胞存活率，GAP43染色观察再生视神经纤维情况，F VEP检测视神经功能。Western Blot检测整合素αv、整合素α5和FAK蛋白的表达。RhoA G LISA法检测RhoA活性。
主要结果和结论如下：
1、免疫组织化学染色方法证实整合素αv、整合素α5以及整合素的下游关键分子FAK均可在大鼠的视皮质、视网膜以及视神经中表达。这些Nogo氨基末端信号通路关键分子表达在视觉通路上，说明Nogo氨基末端有可能通过整合素信号途径发挥作用。
2、Nogo A靶向siRNA可高效特异的下调RGCs的Nogo A的表达，而通用阴性对照序列对Nogo A的表达无影响，成功筛选出有效RNAi序列，为本研究中构建Nogo A靶向siRNA重组腺相关病毒表达载体提供了实验前提。Nogo A靶向siRNA重组腺相关病毒表达载体可有效的抑制原代培养的RGCs以及活体动物视网膜神经节细胞层的Nogo A蛋白的表达，且在动物体内Nogo A的抑制效应于病毒注射后4w即已存在，8w时仍持续，提示重组腺相关病毒已成功的整合到RGCs基因组中，从而可以发挥其长久RNA干扰作用。
3、体外实验采用RNAi完全抑制Nogo A和针对Nogo A的部分片段（Nogo66）的拮抗剂（Nep140）均可促进RGCs轴突生长，但完全抑制Nogo A后促生长作用更强，说明Nogo A上尚存在除Nogo66外的抑制片段，而给予Nogo氨基末端的功能片段△20能够明显抑制RGCs轴突生长，证实Nogo氨基末端即为Nogo A上除Nogo66外的抑制片段。
4、在体动物实验，荧光金逆行标记观察RGCs存活率，发现Nogo氨基末端对RGCs存活的抑制作用，通过生长相关蛋白43（growth associatted protein43, GAP43）免疫荧光组织化学染色观察视神经钳夹伤后视神经再生情况证实Nogo氨基末端抑制神经再生修复；F VEP检测证明Nogo氨基末端不利于视神经功能的恢复，提示Nogo氨基末端抑制视神经再生修复及功能恢复。
5、通过调控Nogo A氨基末端功能片段观察其下游信号通路蛋白整合素αv、整合素α5、FAK和RhoA的表达变化，发现Nogo氨基末端通过整合素αv信号通路发挥抑制作用。
Eyes are organs detecting light and converting it into electro chemical impulses inretina. Retinal ganglion cells (RGCs) axons form the optic nerve (ON), injury of which hasbeen one of the causes of visual loss. Although ON injury accounts for only smallproportion of visual loss, the impaired vision is in general not recoverable. After injury, ONis unable to regenerate, which mainly because that RGCs retrogradely degenerate followinginjury and lack the ability of regenerating axons. Studies showed that the failure of axonsregeneration in adult mammalian central nervous system was partly due to the presence ofendogenous inhibitors of axon regeneration, which include Nogo A, myelin associatedglycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMGP). Among thoseendogenous inhibitors, Nogo A has received much attention. Nogo A is a myelin associatedinhibitor, the function of which depends on its two inhibitory domains:66amino aciddomain (Nogo66) and N terminal domain (Amino Nogo). The Nogo66domain bothinhibits axonal regeneration and regulates axonal growth, guidance and CNS plasticityneurogenesis. Conversely, Amino Nogo only exerts an inhibitory effect. However, the roleand the mechanism of Amino Nogo in the optic nerve have not been fully elucidated.
Integrins are heterodimeric cell surface glycoproteins composed of α and β subunitsthat are non covalently connected. Integrins bind ligands in the extracellular matrix andform adhesion complexes that couple to the actin cytoskeleton. These complexes arenecessary for cellular expansion and axonal growth. Amino Nogo inhibits cell adhesion andaxonal outgrowth by inhibiting integrins, and the effect of Amino Nogo is related todifferent integrin subunits in axonal outgrowth. Integrins αv and α5, are widely expressedin the CNS, however, which integrin subunit is the main player in the Amino Nogo–integrinsignaling pathway operating in axonal outgrowth remains unknown.
The study is divided into three parts:1、Investigating the proteins of Amino Nogosignalling pathway expression in the optic nerve system.2、Investigating the inhibitoryeffect of Amino Nogo on optic nerve regeneration.3、Investigating the Amino Nogo inhibiting RGC axonal outgrowth primarily through the integrin αv signaling pathway, butnot integrin α5signaling pathway.
Aim: To regulat the Amino Nogo to confirm that the Amino Nogo inhibits nerveregeneration. To investigate the mechanism of Amino Nogo inhibiting optic nerveregeneration. To provide a new strategy for the treatment of optic nerve damage, as well asto provide reference for central nervous system injury repair research.
Methods: In this study we detected the expression of integrin αv, integrin α5andfocal adhesion kinase (FAK) by immunohistochemistry. Screening for siRNA sequencetargeting rat Nogo A mRNA in vitro. Production and purification of RecombinantAdenoassociated VirusVectors (rAAV). rAAV2/8NC siRNA, rAAV2/8Nogo A siRNA, apeptide antagonist of Nogo66of Nogo A (Nep140), and a recombinant rat Nogo A Fcchimeric protein (△20) were added in the primary RGCs. The axonal length of RGCs wasassayed by Thy1immunofluorescence stained. We injected PBS, rAAV2/8NC siRNA,rAAV2/8Nogo A siRNA, Nep140and△20in vitreous cavity of the SD rats following opticnerve crush injury and observed the RGCs survival rate by retrograde fluorogold labeling,the number of regenerating axons by GAP43immunofluorescence stained and the opticnerve function recovery by F VEP recording. Western Blot assayed the expression changesof integrin αv, integrin α5and FAK. RhoA activition was measured by RhoA G LISA.
The main results and conclusions are as follows:
1、Integrin αv, integrin α5and focal adhesion kinase (FAK) were widely expressed inthe visual cortex, retina and optic nerve by immunohistochemical staining. TheAmino Nogo–integrin signaling pathway related key proteins expressed in the visualsystem indicating that Amino Nogo plays a role may through the integrin signaling pathway.This study establishes the foundation for further experiments.
2、Our test showed the siRNA targeting to Nogo A could efficiently down regulatedNogo A expression in RGCs, but the control siRNA had no influence on the Nogo A level,which successfully screened effective RNAi sequence and laid the foundation forconstructing the recombinant virus vector. The recombinant virus vector could efficientlyinhibit the Nogo A protein of primary RGCs in vitro. In vivo, the inhibition has beenexisted4weeks after virus injection and maintained till8weeks in retinal ganglion celllayer, which confirmed it had been integrated into RGCs genome and might have longer inhibition
3、In vitro test showed Nogo66antagonist peptide (Nep1–40) promoted RGCsoutgrowth, which indicated Nogo66functional domains can inhibit the outgrowth of RGCs.In addition, Nogo siRNA also promoted axonal outgrowth of RGCs and the length of RGCsaxons were longer than Nep140group, which suggested that except Nogo66functionaldomains can inhibit axonal growth, its other functional domain, Amino Nogo domain, canalso inhibit the outgrowth of RGCs. The recombinant rat Nogo A Fc chimeric protein (△20)can significantly inhibit the RGCs outgrowth, further indicated that Amino Nogo played aninhibitory effect.
4、In vivo test showed Amino Nogo inhibited the survival rate of RGCs by fluoroGoldretrogradely labeled RGC neurons by injecting, and Amino Nogo inhibited nerveregeneration following the optic nerve injury by growth associatted protein43(GAP43)immunofluorescence staining. The F VEP recording also demonstrated that Amino Nogowas harmful to the recovery of optic nerve function. All of the above results suggest thatAmino Nogo inhibits optic nerve regeneration and functional recovery.
5、In vitro and in vivo experiments showed Amino Nogo inhibited optic nerveregeneration through the integrin αv signaling pathway by observing the expressionchanges of integrin αv, integrin α5, FAK and RhoA, which were Amino Nogo signalingpathway downstream proteins.
引文
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