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1.
GDNF来自于小胶质神经元,首先作为中脑多巴胺能神经元的复活因子被发现,可促进细胞存活,并有增加多巴胺神经元细胞大小及轴突长度的作用。GDNF通过与锚定蛋白细胞表面受体糖基磷脂酰肌醇的相互作用来调节细胞活性。GDNF家族a-1受体,通过跨膜酪氨酸受体或者神经元细胞黏附分子,来促进细胞存活,神经突生长,以及突触发育。后续的研究提示,无论未成年还是成体大脑,GDNF对多种神经细胞都有复活的作用,并与一些周围神经复活、迁移、分化相关。不同的脑缺血实验模型均证实了外源性GDNF对于病灶部位及全脑的神经保护作用,包括局部应用营养因子,利用病毒载体运载GDNF基因以及移植表达GDNF的细胞。近来研究还证实,GDNF不仅对多巴胺能神经元,中枢和周围神经系统的运动、感觉神经元,以及自主神经元有营养和保护作用,对于非神经系统也有不同调节作用。本文将重点讨论这些GDNF作用的不同策略以及机制。  相似文献   

2.
GDNF对多巴胺能神经元作用机制的研究进展   总被引:3,自引:0,他引:3  
Pan J  Chen SD 《生理科学进展》2006,37(3):247-251
胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)是神经保护治疗帕金森病(Parkinson's disease,PD)的一种神经营养因子,越来越多的在体和离体实验研究显示GDNF是中脑多巴胺(dopaminergic neuron,DA)能神经元的有效存活因子。GDNF受体是由结合在细胞质膜外的糖基化磷酯酰基(glycosyl-phosphatidylinositol,GPI)和GDNF功能性孤儿受体酪氨酸激酶Ret蛋白质组成。特异性的GDNF与其受体结合后,激活其胞内部分c-Ret,经由不同的第二信使来传递信号发挥作用。主要可能的机制有顺式作用和反式作用。而探索GDNF促进中脑黑质DA能神经元再生修复的可能机制,为进一步深入研究GDNF的作用机制提供科学依据。  相似文献   

3.
GDNF对体外运动神经元和感觉神经元的影响   总被引:5,自引:0,他引:5  
目的:探讨胶质细胞源性神经营养因子(GDNF)对正常胎鼠脊髓运动神经元(SMN)和背根神经节神经元(DRG)生长活性的作用.方法:建立大鼠胚胎SMN和DRG单细胞培养体系,观察1 μg/L、10 μg/L、50 μg/L和100 μg/L GDNF对SMN和DRG存活及突起生长的影响.结果: GDNF组培养的SMN和DRG存活数目明显增加,神经元突起长度比对照组明显增长,且具有剂量依赖趋势.结论: GDNF对正常大鼠胚胎发育期运动神经元和感觉神经元具有神经营养作用.  相似文献   

4.
胶质细胞源性神经营养因子(GDNF)家族是一类结构上属于转化生长因子-β(TGF-β)超家族的神经营养因子,目前包括GDNF,neurturin(NTN)和persephin(PSP)三种因子,它们在体内有着广泛的作用.近年来发现GDNF和NTN的受体均为多组分结构,由不同的糖基磷脂酰肌醇(GPI)蛋白和共享的跨膜酪氨酸激酶受体Ret蛋白构成.有关这一家族的因子及其受体的研究正在不断深入.  相似文献   

5.
胶质细胞源性神经营养因子能够促进多种神经细胞特别是多巴胺能神经元及运动神经元存活。胶质细胞源性神经营养因子的信号传递受体是RET受体酪氨酸激酶,受体α亚基是它与RET相互作用的媒介。胶质细胞源性神经营养因子生物学活性的发挥需要RET与受体α亚基同时存在。  相似文献   

6.
阐述了胶质细胞源性神经营养因子(GDNF)及其受体与精原干细胞增殖和分化的关系。GDNF能够促进未分化的精原细胞增长,并且可以调节精原干细胞自我更新与分化的微环境,参与其分化的第一步,是精原干细胞存活的重要营养因子。  相似文献   

7.
目的观察胶质细胞源性神经营养因子(GDNF)在青年和老年大鼠小脑和海马中的表达特征。方法采用免疫组织化学方法显示GDNF在青年及老年大鼠小脑和海马的分布变化。应用计算机图像分析系统对免疫组织化学反应切片进行检测。结果青年组小脑蒲肯野细胞GDNF阳性反应明显强于老年组;但在青年和老年大鼠海马区,GDNF免疫细胞反应的差别并不明显。结论GDNF在蒲氏细胞内含量的增龄性变化提示它影响蒲肯野细胞及小脑其它神经元的功能与存活,对于小脑神经细胞的老化有重要意义。  相似文献   

8.
本文研究了GDNF对体外培养各个时期的脊髓神经元的作用。通过MTT法检测GDNF对脊髓神经元存活率的影响,发现GDNF能促进培养7天及14天的神经元存活。 通过活体观察、尼氏染色、NSE免疫细胞化学染色观察GDNF对脊髓神经元生长锥数目、胞体大小、突起长度及分枝、侧棘形成的影响,发现GDNF对体外培养1—3周的脊髓神经元有明显的营养作用。  相似文献   

9.
周围神经损伤后外源性GDNF对神经元的保护作用   总被引:3,自引:0,他引:3  
采用硅管套接大鼠切断的坐骨神经模型 ,局部给予胶质细胞源性神经营养因子 (GDNF) ,应用尼氏染色、酶组织化学染色方法 ,观察到外源性GDNF能减少脊髓修复侧前角运动神经元死亡的数目 ,降低脊髓前角运动神经元及脊神经节感觉神经元中胆碱酯酶 (CHE)及酸性磷酸酶 (ACP)变化的幅度。这表明外源性GDNF能保护周围神经切断后引起的神经元损伤。  相似文献   

10.
为了研究胶质细胞源性神经营养因子(GDNF)在中枢神经系统疾病中的治疗应用,运用基因突变、蛋白质融合表达和蛋白质纯化技术获得分子质量较小的GDNF(△N39)活性片段.将HIV-1 Tat蛋白转导区(protein transduction domain,PTD)的9个碱性氨基酸49RKKRRQRRR57模拟物9个精氨酸(R9)与GDNF(△N39)活性片段融合表达,获得纯度达95%以上的GDNF(△N39)-R9融合蛋白.将GDNF、GDNF(△N39)、GDNF(△N39)-R9分别加入原代培养的中脑多巴胺能神经元和转染GDNF受体GFRαl和Ret的PC12细胞中,观察它们的神经营养活性和毒性.运用脑微血管内皮细胞株B-Endo 3,观察GDNF(△N39)-R9蛋白穿越血管内皮细胞膜的功能;运用脑血管内皮细胞和Matrigel铺板模拟血脑屏障,Transwell法检测Tat-GDNF(△N39)蛋白穿越脑血管内皮细胞和外周胶质膜的能力.结果显示:GDNF(△N39)-R9蛋白具有类似GDNF的神经营养活性,促进原代培养的中脑多巴胺能神经元和稳定表达GFRα1和Ret受体的PC12-GFRα1-Ret细胞株的存活,没有显示毒性,并且能很好地穿过脑微血管内皮细胞层和模拟的血脑屏障.  相似文献   

11.
Nerve growth factor induces P2X(3) expression in sensory neurons   总被引:3,自引:0,他引:3  
Glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) are neuroprotective for subpopulations of sensory neurons and thus are candidates for pain treatment. However, delivering these factors to damaged neurons will invariably result in undamaged systems also being treated, with possible consequences for sensory processing. In sensory neurons the purinergic receptor P2X(3) is found predominantly in GDNF-sensitive nociceptors. ATP signalling via the P2X(3) receptor may contribute to pathological pain, suggesting an important role for this receptor in regulating nociceptive function. We therefore investigated the effects of intrathecal GDNF or NGF on P2X(3) expression in adult rat spinal cord and dorsal root ganglia (DRG). In control spinal cords, P2X(3) expression was restricted to a narrow band of primary afferent terminals within inner lamina II (II(i)). Glial cell line-derived neurotrophic factor treatment increased P2X(3) immunoreactivity within lamina II(i) but not elsewhere in the cord. Nerve growth factor treatment, however, induced novel P2X(3) expression, with intense immunoreactivity in axons projecting to lamina I and outer lamina II and to the ventro-medial afferent bundle beneath the central canal. In the normal DRG, we found a greater proportion of P2X(3)-positive neurons at cervical levels, many of which were large-diameter and calcitonin gene-related peptide-positive. In both cervical and lumbar DRG, the number of P2X(3)-positive cells increased following GDNF or NGF treatment. De novo expression of P2X(3) in NGF-sensitive nociceptors may contribute to chronic inflammatory pain.  相似文献   

12.
Dexmedetomidine (DEX) has been found to improve neuronal survival after transient global or focal cerebral ischemia in rats. Astrocyte cells may possess beneficial properties that promote neuronal recovery by secreting neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF). The purpose of this study was to investigate the effects of DEX on GDNF release from astrocytes and the possible mechanisms involved. Astrocyte cells were treated with DEX, and GDNF level in the conditioned media was determined by ELISA assay. The expression of CREB, p-CREB and PKCα was analyzed by Western blotting to explore the mechanisms involved in GDNF release. Our results showed that DEX stimulated GDNF release in a time- and dose-dependent manner; and this stimulation was blocked by the α2-adrenoreceptor antagonist yohimbine, but not by α1-adrenoreceptor antagonist prasozin, demonstrating that DEX induced GDNF release likely acts via activating the α2A adrenoreceptor. In addition, DEX-stimulated GDNF release was also blocked by the universal PKC inhibitor Ro-318220 and PKCα/β inhibitor G? 6976, but not by PKCδ inhibitor rottlerin and PKCβ inhibitor LY333531. Interestingly, DEX also activated CREB phosphorylation, which was inhibited by Ro-318220, G? 697 and ERK kinase inhibitor PD98059. Silencing CREB by siRNA decreased the DEX-stimulated GDNF release. In addition, the membrane translocation of PKCα was enhanced following DEX treatment. Furthermore, we found that DEX stimulated GDNF release rescued neurons against OGD-induced neurotoxicity; this effect was partly abolished by GDNF antibody. Thus, through α2A adrenergic receptors, DEX may activate astrocytes, and promote GDNF release to protect neurons after stroke, and this signaling is possibly dependent on PKCα and CREB activation.  相似文献   

13.
Malin SA  Davis BM 《生理学报》2008,60(5):571-578
The neurotrophin and glial cell line-derived neurotrophic factor (GDNF) family of growth factors have been extensively studied because of their proven ability to regulate development of the peripheral nervous system. The neurotrophin family,which includes nerve growth factor (NGF), NT-3, NT4/5 and BDNF, is also known for its ability to regulate the function of adult sensory neurons. Until recently, little was known concerning the role of the GNDF-family (that includes GDNF, artemin, neurturin and persephin) in adult sensory neuron function. Here we describe recent data that indicates that the GDNF family can regulate sensory neuron function, that some of its members are elevated in inflammatory pain models and that application of these growth factors produces pain in vivo. Finally we discuss how these two families of growth factors may converge on a single membrane receptor, TRPV 1, to produce long-lasting hyperalgesia.  相似文献   

14.
Glial cell-line derived neurotrophic factor (GDNF) is a potent survival factor for motor neurons. Previous studies have shown that some motor neurons depend upon GDNF during development but this GDNF-dependent motor neuron subpopulation has not been characterized. We examined GDNF expression patterns in muscle and the impact of altered GDNF expression on the development of subtypes of motor neurons. In GDNF hemizygous mice, motor neuron innervation to muscle spindle stretch receptors (fusimotor neuron innervation) was decreased, whereas in transgenic mice that overexpress GDNF in muscle, fusimotor innervation to muscle spindles was increased. Facial motor neurons, which do not contain fusimotor neurons, were not changed in number when GDNF was over expressed by facial muscles during their development. Taken together, these data indicate that fusimotor neurons depend upon GDNF for survival during development. Since the fraction of cervical and lumbar motor neurons lost in GDNF-deficient mice at birth closely approximates the size of the fusimotor neuron pool, these data suggest that motor neuron loss in GDNF-deficient mice may be primarily of fusimotor neuron origin.  相似文献   

15.
Glial cell line-derived neurotrophic factor (GDNF), a member of the GDNF family of neurotrophic factors, promotes the survival and function of several neuronal populations in the peripheral and central nervous system. In the present study, expression of GDNF mRNA in the shaft of adult rat penis is demonstrated. In situ hybridization revealed GDNF mRNA expression in cells lying in the narrow zone between the tunica albuginea and the cavernous tissue. Most subtunical cells exhibited immunoreactivity for vimentin and S100 beta, but they did not stain for smooth muscle alpha actin or PGP9.5. This suggests that the GDNF mRNA-expressing cells may have a mesenchymal origin. Also retrograde axonal transport of intracavernously injected 125I-labeled GDNF in penile parasympathetic and sensory neurons is shown. The transport was inhibited by excess unlabeled GDNF, whereas excess cytochrome c had no effect. This is in agreement with the view that the transport was mediated by binding to specific receptors located on axon terminals. In addition, this study demonstrates expression of GDNF family receptor-alpha 3 (GFR alpha 3) mRNA in most adrenergic, but only in a minor part (5.3%) of the penis-projecting adult rat major pelvic ganglion neurons, as well as in almost half (45.6%) of the penile S1 dorsal root ganglion neurons. In conclusion, the present data suggest that GDNF may act as a neurotrophic factor for subpopulations of adult rat penile parasympathetic and sensory neurons.  相似文献   

16.
Neurturin (NTN) and glial cell line-derived neurotrophic factor (GDNF), two members of the GDNF family of growth factors, exert very similar biological activities in different systems, including the substantia nigra. Our goal in the present work was to compare their function and define whether nonoverlapping biological activities on midbrain dopaminergic neurons exist. We first found that NTN and GDNF are differentially regulated during postnatal development. NTN mRNA progressively decreased in the ventral mesencephalon and progressively increased in the striatum, coincident with a decrease in GDNF mRNA expression. This finding suggested distinct physiological roles for each factor in the nigrostriatal system. We therefore examined their function in ventral mesencephalon cultures and found that NTN promoted survival comparable with GDNF, but only GDNF induced sprouting and hypertrophy of developing dopaminergic neurons. We subsequently examined the ability of NTN to prevent the 6-hydroxydopamine-induced degeneration of adult dopaminergic neurons in vivo. Fibroblasts genetically engineered to deliver high levels of GDNF or NTN were grafted supranigrally. NTN was found to be as potent as GDNF at preventing the death of nigral dopaminergic neurons, but only GDNF induced tyrosine hydroxylase staining, sprouting, or hypertrophy of dopaminergic neurons. In conclusion, our results show selective survival-promoting effects of NTN over wider survival, neuritogenic, and hypertrophic effects of GDNF on dopaminergic neurons in vitro and in vivo. Such differences are likely to underlie unique roles for each factor in postnatal development and may ultimately be exploited in the treatment of Parkinson's disease.  相似文献   

17.
Glial cell line-derived neurotrophic factor (GDNF) is expressed in the gastrointestinal tract of the developing mouse and appears to play an important role in the migration of enteric neuron precursors into and along the small and large intestines. Two other GDNF family members, neurturin and artemin, are also expressed in the developing gut although artemin is only expressed in the esophagus. We examined the effects of GDNF, neurturin, and artemin on neural crest cell migration and neurite outgrowth in explants of mouse esophagus, midgut, and hindgut. Both GDNF and neurturin induced neural crest cell migration and neurite outgrowth in all regions examined. In the esophagus, the effect of GDNF on migration and neurite outgrowth declined with age between E11.5 and E14.5, but neurturin still had a strong neurite outgrowth effect at E14.5. Artemin did not promote neural migration or neurite outgrowth in any region investigated. The effects of GDNF family ligands are mediated by the Ret tyrosine kinase. We examined the density of neurons in the esophagus of Ret-/- mice, which lack neurons in the small and large intestines. The density of esophageal neurons in Ret-/- mice was only about 4% of the density of esophageal neurons in Ret+/- and Ret+/+ mice. These results show that GDNF and neurturin promote migration and neurite outgrowth of crest-derived cells in the esophagus as well as the intestine. Moreover, like intestinal neurons, the development of esophageal neurons is largely Ret-dependent.  相似文献   

18.
19.
Although glial cell-line derived neurotrophic factor (GDNF) acts as a potent survival factor for dopaminergic neurons, it is not known whether GDNF can directly alter dopamine synthesis. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for dopamine biosynthesis, and its activity is regulated by phosphorylation on three seryl residues: Ser-19, Ser-31, and Ser-40. Using a TH-expressing human neuroblastoma cell line and rat primary mesencephalic neuron cultures, the present study examined whether GDNF alters the phosphorylation of TH and whether these changes are accompanied by increased enzymatic activity. Exposure to GDNF did not alter the TH protein level in either neuroblastoma cells or in primary neurons. However, significant increases in the phosphorylation of Ser-31 and Ser-40 were detected within minutes of GDNF application in both cell types. Enhanced Ser-31 and Ser-40 phosphorylation was associated with increased TH activity but not dopamine synthesis in neuroblastoma cells, possibly because of the absence of l-aromatic amino acid decarboxylase activity in these cells. In contrast, increased phosphorylation of Ser-31 and Ser-40 was found to enhance dopamine synthesis in primary neurons. Pharmacological experiments show that Erk and protein kinase A phosphorylate Ser-31 and Ser-40, respectively, and that their inhibition blocked both TH phosphorylation and activity. Our results indicate that, in addition to its role as a survival factor for dopaminergic neurons, GDNF can directly increase dopamine synthesis.  相似文献   

20.
Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN) are neurotrophic factors for parasympathetic neurons including ciliary ganglion (CG) neurons. Recently, we have shown that survival and signaling mediated by GDNF in CG neurons essentially requires transforming growth factor β (TGFβ). We have provided evidence that TGFβ regulates the availability of the glycosyl phosphatidylinositol (GPI)-anchored GDNF receptor alpha 1 (GFRα1) by promoting the recruitment of the receptor to the plasma membrane. We report now that in addition to GDNF, NRTN, but not persephin (PSPN) or artemin (ARTN), is able to promote survival of CG neurons. Interestingly, in contrast to GDNF, NRTN is not dependent on cooperation with TGFβ, but efficiently promotes neuronal survival and intracellular signaling in the absence of TGFβ. Additional treatment with TGFβ does not further increase the NRTN response. Both NRTN and GDNF exclusively bind to and activate their cognate receptors, GFRα2 and GFRα1, respectively, as shown by the use of receptor-specific neutralizing antibodies. Immunocytochemical staining for the two receptors on the surface of CG neurons reveals that, in contrast to the effect on GFRα1, TGFβ is not required for recruitment of GFRα2 to the plasma membrane. Moreover, binding of radioactively labeled GDNF but not NRTN is increased upon treatment of CG neurons with TGFβ. Disruption of TGFβ signaling does interfere with GDNF-, but not NRTN-mediated signaling and survival. We propose a model taking into account data from GFRα1 crystallization and ontogenetic development of the CG that may explain the differences in TGFβ-dependence of GDNF and NRTN.  相似文献   

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