Retrograde axonal transport of glial cell line-derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult.
Retrograde axonal transport of glial cell line-derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult.
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DOI：
10.1073/pnas.92.18.8274
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发表时间：
1995-08
影响因子：
11.1
通讯作者：
A. Tomac;J. Widenfalk;Leu‐Fen H. Lin;Tadahiko Kohno;Ted Ebendal;Barry J. Hoffer;Lars Olson
中科院分区：
文献类型：
--
作者：
A. Tomac;J. Widenfalk;Leu‐Fen H. Lin;Tadahiko Kohno;Ted Ebendal;Barry J. Hoffer;Lars Olson
最近克隆的转化生长因子（tgf - β）家族的远亲，神经胶质细胞系来源的神经营养因子（GDNF），对胎儿中脑多巴胺神经元有强大的营养作用。GDNF还对成年中脑多巴胺能神经元具有保护和恢复作用，并能有效地保护运动神经元免受axotomy诱导的细胞死亡。然而，内源性GDNF作为靶源性营养因子在成人中脑多巴胺能回路中发挥作用的证据，需要记录从靶区合成部位到神经细胞体本身的特定运输。在这里，我们证明了GDNF是由黑质纹状体途径的中脑多巴胺神经元逆行运输的。纹状体内注射后的逆行转运模式表明可能存在对GDNF有反应的神经元亚群。具有生物活性的125i标记GDNF的轴突逆行转运受到过量未标记GDNF的抑制，但不受过量细胞色素c的抑制。通过证明另一个tgf - β家族成员tgf - β 1似乎不影响逆行转运，进一步证明了特异性。使用未标记的GDNF在胃内注射，免疫组织化学也证实了逆行转运。GDNF免疫反应性特异出现在黑质致密部多巴胺神经细胞体中，呈颗粒状分布于体细胞和近端树突。我们的数据暗示了一种特定的受体介导的摄取机制在成人中运作。综上所述，目前的研究结果表明，GDNF作为多巴胺能神经元的靶源性生理生存/维持因子内源性起作用。
The recently cloned, distant member of the transforming growth factor beta (TGF-beta) family, glial cell line-derived neurotrophic factor (GDNF), has potent trophic actions on fetal mesencephalic dopamine neurons. GDNF also has protective and restorative activity on adult mesencephalic dopaminergic neurons and potently protects motoneurons from axotomy-induced cell death. However, evidence for a role for endogenous GDNF as a target-derived trophic factor in adult midbrain dopaminergic circuits requires documentation of specific transport from the sites of synthesis in the target areas to the nerve cell bodies themselves. Here, we demonstrate that GDNF is retrogradely transported by mesencephalic dopamine neurons of the nigrostriatal pathway. The pattern of retrograde transport following intrastriatal injections indicates that there may be subpopulations of neurons that are GDNF responsive. Retrograde axonal transport of biologically active 125I-labeled GDNF was inhibited by an excess of unlabeled GDNF but not by an excess of cytochrome c. Specificity was further documented by demonstrating that another TGF-beta family member, TGF-beta 1, did not appear to affect retrograde transport. Retrograde transport was also demonstrated by immunohistochemistry by using intrastriatal injections of unlabeled GDNF. GDNF immunoreactivity was found specifically in dopamine nerve cell bodies of the substantia nigra pars compacta distributed in granules in the soma and proximal dendrites. Our data implicate a specific receptor-mediated uptake mechanism operating in the adult. Taken together, the present findings suggest that GDNF acts endogenously as a target-derived physiological survival/maintenance factor for dopaminergic neurons.