Slit2在部分神经系统疾病中的研究

<正>神经导向因子Slit是一种分泌型细胞外基质蛋白,轴突生长导向因子,具有促进轴突分支和控制神经元迁移的作用~[1]。目前,在哺乳动物中已明确的Slit家族成员包括三种亚型的Slit(Slit1,Slit2,Slit3)和其四种形式的受体Robo(Robo1,Robo2,Robo3,Robo4)~[2]。其中,Slit2是Slit家族的一员,在改变血管通透性,调节肿瘤细胞迁移和新生血管形成,调节白细胞及内皮细胞的迁移,抑制炎症递质的释放,调节心脏的发育中发挥重要的生物学作用。本文就Slit2与部分神经     

Slit2/Robo1信号通路在神经胶质瘤侵袭与迁移中的作用(英文)

Slit2/Robo1信号通路是一个进化保守的配体受体系统。该信号通路对神经细胞的分布、迁移、轴突导向起着重要作用。Slit2及其跨膜受体Robo1蛋白在胶质瘤中的分布是不同的。Slit2在毛细胞性星形细胞瘤及胶质母细胞瘤中是低表达的,而Robo1在各级别的胶质瘤中均有高表达。恶性胶质瘤细胞的浸润侵袭机制包括多条信号通路的多种基因的改变。虽然Slit2/Robo1信号通路抑制肿瘤的分子机制尚不清楚,但已有研究报道其抑制胶质瘤细胞侵袭的作用是通过抑制Cdc42-GTP的活性来实现的。本文主要就Slit2/Robo1信号通路在胶质瘤中的作用进行详尽探讨。伴随Slit2/Robo1信号通路分子机制研究的不断深入,将会为有效治疗恶性胶质瘤提供新的策略和思路。     

Slit：一种新的神经生长导向因子

神经纤维生长和神经细胞迁移的靶位导向是神经发育和再生研究的基本问题之一。轴突和神经元朝靶部位的定向移动是在神经生长导向因子的协同作用下完成的。Sit是最近发现的第一种对轴突生长和神经元迁移都有导向作用的因子。它对神经生长的导向作用是神经发育和再生研究领域的重大突破。已经证明,Slit还能促进背根神经节轴突的延伸和分枝,抑制白细胞的化学趋向性运动。     

Wnt信号与神经干细胞分化

背景：研究表明，移植入宿主体内的神经干细胞可分化为神经元或神经胶质细胞。Wnt信号通路与神经干细胞的分化密切相关。通过调节Wnt信号通路可控制神经干细胞的定向分化。 目的：对神经干细胞分化及其与Wnt信号通路的关系进行综述. 方法：应用计算机检索2002-02/2010-03 Medline数据库、Ovid数据库、CNKI、EBSCO数据库与神经干细胞相关文献。检索词为“神经干细胞，神经再生，Wnt信号，神经元，分化”。纳入与神经干细胞分化及Wnt信号系统相关文献，排除重复性研究，保留30篇文献进行综述。 结果与结论：神经干细胞是一类具有自我更新和多向分化潜能的细胞，能分化形成机体中枢神经系统几乎所有类型的细胞。Wnt信号通路在神经干细胞的分化中起重要作用。文章从神经干细胞、Wnt信号通路、Wnt信号通路与神经干细胞的分化等方面分别进行了叙述。然而，Wnt信号通路控制神经干细胞分化的具体机制还不是很清楚。     

Slit3在缺血性脑卒中血管生成中的作用研究进展

<正>缺血性脑卒中是人类致残甚至死亡的主要疾病之一,颅内神经元是不可再生细胞,但脑血管却可以再生,因此恢复脑血流、促进血管再生对脑功能恢复至关重要。轴突导向分子Slit3是近年来发现的分泌型细胞外基质蛋白。最近的研究表明,Slit3是一种新的血管生成因子,涉及调节各种生命活动如细胞迁移、血管生成、器官发生、生殖调节、肿瘤发生和精神疾病。Slit3对血管方面的作用为我们进一步研究及了解其在血管生成中的机制提供重要依据,也为缺血性脑血管病的治疗提     

Sonic Hedgehog信号通路及其对神经系统的影响

正Sonic Hedgehog(Shh)信号通路是调节机体生长等关键环节的主要的信号通路之一[1],其传导途径是近年来研究的热点。Shh作为信号分子已被证实参与中枢神经系统的调节和神经发生[2],目前国内外许多研究证实Shh信号通路与脑缺血后神经修复有关,可在大脑神经元可塑性方面起调节作用,从而降低缺血性脑损伤导致的细胞凋亡[3]。Shh信号通路可调节细胞的有丝分裂过程,参与肿瘤的发生、发展和转     

突触后支架蛋白与神经退行性疾病

突触后致密物质作为神经元兴奋性突触后膜上的特殊结构,在神经元功能调节中具有重要作用。PSD-95、Shank、Homer是突触后致密物质中重要的支架蛋白,参与调节神经元信号传导、突触可塑性等过程,与神经系统疾病的发生和发展密切相关。该文就突触后支架蛋白在阿尔兹海默症、帕金森病等神经退行性疾病中的作用及机制进行综述,以此探讨突触后支架蛋白及其相关信号通路作为神经退行性疾病靶点治疗的可能性。     

胶质源性神经营养因子神经保护作用的研究进展

胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)是神经营养因子的一种,具有促进多巴胺能神经元再生、修复与营养神经元、调控细胞周期等作用。GDNF通过受体复合物的形式介导其信号通路,从而产生生物学效应。其主要细胞内信号转导通路有丝裂原活化蛋白激酶/细胞外信号调节激酶(MAPK/ERK)通路与磷酯酰肌醇-3激酶/蛋白激酶B(PI3K/Akt)信号通路。大量研究证实,GDNF在帕金森病、缺血性脑血管疾病、周围神经疾病等多种神经系统疾病中均具有神经保护作用,是神经科学尤其是帕金森病等神经退行性疾病治疗研究的新方向。     

人脑胶质瘤miR-218和Robo1的表达及意义

目的研究人脑胶质瘤微小核糖核苷酸-218(mi R-218)和Robo1的表达及意义。方法选取Ⅰ和Ⅱ级胶质瘤患者的脑组织10例,行颅内减压的正常脑组织10例、Ⅲ级胶质瘤脑组织10例、Ⅳ级肿瘤脑组织10例,使用实时荧光定量PCR(q RT-PCR)检测微小RNA218的表达量,采用免疫组织化学和WB的方法检测组织中Slit2蛋白和Robo1蛋白的表达水平,分析mi R-218与Slit2-Robo1通路的关系。结果从正常组织、低级别胶质瘤到高级别胶质瘤,其微小RNA218、Slit2联合Robo1的表达量依次降低,Robo1的表达逐渐升高。结论当肿瘤组织中微小RNA218的表达减少时,Slit2蛋白的表达也同时降低,而Robo1蛋白的表达则异常增高,3种物质的水平与肿瘤的良恶程度有重要关系。     

人脑膜瘤组织Slit2、Robo1的表达与术后复发的关系

目的 探讨人脑膜瘤Slit、Robo的表达与术后复发的关系。方法 收集2016年1月至2021年4月手术切除的脑膜瘤104例,另选取颅脑损伤内减压术切除的非肿瘤脑组织50例（对照组）,用免疫组织化学染色法检测Slit2、Robo1的表达水平。术后随访1年,判断肿瘤复发情况。结果 104例中,术后1年复发22例,复发率为21.15%。脑膜瘤组织Slit2低表达率[37.50%(39/104)]明显低于对照组[70.00%(35/50);P<0.05]。脑膜瘤组织Robo1高表达率[59.61%(62/104)]明显高于对照组[34.00%(17/50);P<0.05]。多因素logsitic回归分析显示,Slit2低表达、Robo1高表达是脑膜瘤术后复发的独立危险因素（P<0.05）。结论 脑膜瘤组织Slit2呈低表达,而Robo1呈高表达,二者均与术后复发有关。     

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFalpha application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal-glial cultures subjected to oxygen-glucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte-endothelial adherence occurring 4 h after TNFalpha and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFalpha. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal-glial cultures exposed to oxygen-glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy.     

Slit promotes branching and elongation of neurites of interneurons but not projection neurons from the developing telencephalon

Proper neuronal migration and establishment of circuitry are key processes for laying down the functional network of cortical neurons. A variety of environmental guidance cues, attractive or repulsive, have been shown to guide cell migration and axon arborization. One of these, Slit, appears to possess contrarian properties; it can either inhibit axon outgrowth or promote branching and elongation. The object of the present study was to assess the effect of Slit on MGE and neocortical neurons in culture and in the developing ventricle. When cocultured with a Slit source, E13.5 MGE explants displayed inhibited neurite outgrowth while GABA neuron dispersion away from Slit was increased. Similar inhibition of neurite outgrowth was seen in dissociated cells from E13.5 MGE, these cells were identified to be interneurons based upon their GABA staining. In contrast, E13.5 interneurons, after culture for another 5 days, were responsive to Slit by neurite branching and elongation. Projection neurons, identified by lack of GABA staining, did not respond to Slit, either by branching or elongation. Furthermore, GABA interneurons but not pyramidal neurons, appeared to avoid neocortical areas close to an implanted source of Slit in the ventricular wall. These results lead us to suggest that interneurons but not projection neurons are responsive to the chemorepellant effect of Slit. However, more mature interneurons appear to respond to Slit by neurite arborization. These results demonstrate a selective response to Slit by GABAergic neurons during neocortical development.     

Repulsive migration of schwann cells induced by slit‐2 through Ca2+‐dependent RhoA‐Myosin signaling

Schwann cells migrate along axons before initiating myelination during development and their migration facilitates peripheral nerve regeneration after injury. Axon guidance molecule Slit‐2 is highly expressed during peripheral development and nerve regeneration; however, whether Slit‐2 regulates the migration of Schwann cells remains a mystery. Here we show that Slit‐2 receptor Robo‐1 and Robo‐2 were highly expressed in Schwann cells in vitro and in vivo. Using three distinct migration assays, we found that Slit‐2 repelled the migration of cultured Schwann cells. Furthermore, frontal application of a Slit‐2 gradient to migrating Schwann cells first caused the collapse of leading front, and then reversed soma translocation of Schwann cells. The repulsive effects of Slit‐2 on Schwann cell migration depended on a Ca²⁺ signaling release from internal stores. Interestingly, in response to Slit‐2 stimulation, the collapse of leading front required the loss of F‐actin and focal adhesion, whereas the subsequent reversal of soma translocation depended on RhoA‐Rock‐Myosin signaling pathways. Taken together, we demonstrate that Slit‐2 repels the migration of cultured Schwann cells through RhoA‐Myosin signaling pathways in a Ca²⁺‐dependent manner.     

Regulated formation and selection of neuronal processes underlie directional guidance of neuronal migration

Axon guidance and neuronal migration are critical features of neural development, and it is believed that extracellular gradients of secreted guidance cues play important roles in pathfinding. It has been well documented that the growth cones of extending axons respond to such extracellular gradients by growing toward or away from the source of the secreted cue via asymmetrical extension of a single growth cone. However, it is unclear whether migrating neurons change direction in response to guidance molecules using the same mode of turning as extending axons. In this study, we demonstrate that migrating neurons turn away from the chemo-repellent Slit through repeated rounds of process extension and retraction and do not turn through the reorientation of a single growth cone. We further show that Slit increases the rate of somal process formation and that these processes form preferentially on the side of the cell body furthest away from the Slit source. In addition, Slit causes cell turning through asymmetric process selection. Finally, we show that multiple types of migrating neurons employ this mode of cell turning in response to a variety of guidance cues. These results show that migrating neurons employ a unique type of turning when faced with secreted guidance cues that is distinct from the type employed by axons.     

Slit2/Robo1 signaling in glioma migration and invasion

Slit2/Robo1 is a conserved ligand-receptor system, which greatly affects the distribution, migration, axon guidance and branching of neuron cells. Slit2 and its transmembrane receptor Robo1 have different distribution patterns in gliomas. The expression of Slit2 is at very low levels in pilocytic astrocytoma, fibrillary astrocytoma and glioblastoma, while Robo1 is highly expressed in different grades of gliomas at both mRNA and protein levels. Acquisition of insidious invasiveness by malignant glioma cells involves multiple genetic alterations in signaling pathways. Although the specific mechanisms of tumor-suppressive effect of Slit2/Robo1 have not been elucidated, it has been proved that Slit2/Robo1 signaling inhibits glioma cell migration and invasion by inactivation of Cdc42-GTP. With the research development on the molecular mechanisms of Slit2/Robo1 signaling in glioma invasion and migration, Slit2/Robo1 signaling may become a potential target for glioma prevention and treatment.     

Role of trophic factors on neuroimmunity in neurodegenerative infectious diseases

Viral infection of the central nervous system elicits a myriad of cellular, vascular, and neuroimmune factors that contribute to acute, subacute, and chronic damage to the brain. In response to cellular damage, the host is capable of producing trophic factors that may protect neuronal, glial, and endothelial cell populations. Both neurotrophic and angiotrophic factors can also operate by modulating the neuroimmune response, which plays a central role in the pathogenesis of the neurodegenerative process. In this regard, crosstalk signaling among host cells, components of the neuroimmune response, and virus could influence cell fate by production of trophic factors that protect or rescue neurons vulnerable to viral damage. In this context, the main objective of this review is to provide an overview of evidence in support of the role of trophic factors in regulating the neuroimmune response in chronic viral infections of the central nervous system. Special emphasis is placed on the interaction of the human immunodeficiency virus (HIV) Tat protein with endothelial, astroglial, microglial, and neuronal cells, resulting in altered expression of vascular endothelial growth factor, fibroblast growth factor, interleukin-8, and regulation of calcium flux via CXCR2, which directly influences neuronal cell fitness.     

Development of precerebellar nuclei: instructive factors and intracellular mediators in neuronal migration, survival and axon pathfinding

The precerebellar system provides an interesting model to study tangential migrations. All precerebellar neurons (PCN) are generated in the most alar part of the hindbrain in a region called rhombic lip. PCN first emit a leading process and then translocate their nuclei inside it, a mechanism called nucleokinesis. In the past few years, molecular cues that could affect those processes have been investigated, with a special care on: (i) the identification of extrinsic factors directing cell migration and axon elongation as well as neuronal survival during development; (ii) intracellular reorganizations of the cytoskeleton during nucleokinesis in response to chemotropic factors. The signaling cascades, including regulators of actin and microtubule cytoskeleton, in response to diffusible guidance factors have raised an increasing attention. We will here review the role of guidance cues involved in PCN migration in particular netrin-1, Slit and Nr-CAM. We will also consider Rho-GTPases that have been proposed to mediate axon outgrowth and neuronal migration, especially in response to netrin-1, and which may act as a relay between extracellular signals and intracellular remodeling. Recent findings from in vitro pharmacological inhibition of various Rho-GTPases and over-expression of effectors bring molecular cues that, in accordance with anatomical data, fit the idea that nucleokinesis and axon outgrowth are not strictly coupled events during PCN migration.     

Expression and function of the receptor protein tyrosine phosphatase zeta and its ligand pleiotrophin in human astrocytomas

Using subtractive cloning combined with cDNA array analysis, we previously identified the genes encoding for the protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta (PTPzeta/RPTPbeta) and its ligand pleiotrophin (PTN) as overexpressed in human glioblastomas compared to normal brain. Both molecules have been implicated in neuronal migration during central nervous system development, and PTN is known to be involved in tumor growth and angiogenesis. We confirm overexpression of both molecules at the protein level in astrocytic gliomas of different malignancy grades. PTPzeta/RPTPbeta immunoreactivity was associated with increasing malignancy grade and localized predominantly to the tumor cells. PTN immunoreactivity as determined by ELISA and immunohistochemistry analysis was increased in low-grade astrocytomas compared to normal brain. Further increase in malignant gliomas was marginal, and thus no correlation with malignancy grade or microvessel density was present. However, PTN levels were significantly associated with those of fibroblast growth factor-2, suggesting co-regulation of both factors. Functionally, PTN induced weak chemotactic and strong haptotactic migration of glioblastoma and cerebral microvascular endothelial cells. Haptotaxis of glioblastoma cells towards PTN was specifically inhibited by an anti-PTPzeta/RPTPbeta antibody. Our findings suggest that upregulated expression of PTN and PTPzeta/RPTPbeta in human astrocytic tumor cells can create an autocrine loop that is important for glioma cell migration. Although PTN is a secreted growth factor, it appears to exert its mitogenic effects mostly in a matrix-immobilized form, serving as a substrate for migrating tumor cells.     

Cell-autonomous and cell-to-cell signalling events in normal and altered neuronal migration

The cerebral cortex is a complex six-layered structure that contains an important diversity of neurons, and has rich local and extrinsic connectivity. Among the mechanisms governing the cerebral cortex construction, neuronal migration is perhaps the most crucial as it ensures the timely formation of specific and selective neuronal circuits. Here, we review the main extrinsic and extrinsic factors involved in regulating neuronal migration in the cortex and describe some environmental factors interfering with their actions.     

Dynamic expression of Slit1–3 and Robo1–2 in the mouse peripheral nervous system after injury

The Slit family of axon guidance cues act as repulsive molecules for precise axon pathfinding and neuronal migration during nervous system development through interactions with specific Robo receptors.Although we previously reported that Slit1–3 and their receptors Robo1 and Robo2 are highly expressed in the adult mouse peripheral nervous system,how this expression changes after injury has not been well studied.Herein,we constructed a peripheral nerve injury mouse model by transecting the right sciatic nerve.At 14 days after injury,quantitative real-time polymerase chain reaction was used to detect mRNA expression of Slit1–3 and Robo1–2 in L4–5 spinal cord and dorsal root ganglia,as well as the sciatic nerve.Immunohistochemical analysis was performed to examine Slit1–3,Robo1–2,neurofilament heavy chain,F4/80,and vimentin in L4–5 spinal cord,L4 dorsal root ganglia,and the sciatic nerve.Co-expression of Slit1–3 and Robo1–2 in L4 dorsal root ganglia was detected by in situ hybridization.In addition,Slit1–3 and Robo1–2 protein expression in L4–5 spinal cord,L4 dorsal root ganglia,and sciatic nerve were detected by western blot assay.The results showed no significant changes of Slit1–3 or Robo1–2 mRNA expression in the spinal cord within 14 days after injury.In the dorsal root ganglion,Slit1–3 and Robo1–2 mRNA expression were initially downregulated within 4 days after injury;however,Robo1–2 mRNA expression returned to the control level,while Slit1–3 mRNA expression remained upregulated during regeneration from 4–14 days after injury.In the sciatic nerve,Slit1–3 and their receptors Robo1–2 were all expressed in the proximal nerve stump;however,Slit1,Slit2,and Robo2 were barely detectable in the nerve bridge and distal nerve stump within 14 days after injury.Slit3 was highly ex-pressed in macrophages surrounding the nerve bridge and slightly downregulated in the distal nerve stump within 14 days after injury.Robo1 was upregulated in vimentin-positive cells and migrating Schwann cells inside the nerve bridge.Robo1 was also upregulated in Schwann cells of the distal nerve stump within 14 days after injury.Our findings indicate that Slit3 is the major ligand expressed in the nerve bridge and distal nerve stump during peripheral nerve regeneration,and Slit3/Robo signaling could play a key role in peripheral nerve repair after injury.This study was approved by Plymouth University Animal Welfare Ethical Review Board (approval No.30/3203) on April 12,2014.