Glial Cell Line-Derived Neurotrophic Factor Rescues Target-Deprived Sympathetic Spinal Cord Neurons But Requires Transforming Growth Factor-β as Cofactor In Vivo
Glial Cell Line-Derived Neurotrophic Factor Rescues Target-Deprived Sympathetic Spinal Cord Neurons But Requires Transforming Growth Factor-β as Cofactor In Vivo
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DOI：
10.1523/jneurosci.19-06-02008.1999
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发表时间：
1999-03
期刊：
影响因子：
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通讯作者：
A. Schober;R. Hertel;U. Arumäe;L. Farkas;J. Jászai;K. Krieglstein;M. Saarma;K. Unsicker
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文献类型：
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作者：
A. Schober;R. Hertel;U. Arumäe;L. Farkas;J. Jászai;K. Krieglstein;M. Saarma;K. Unsicker
胶质细胞源性神经营养因子(GDNF)是一种对多种中枢神经系统和外周神经元都有效的神经营养因子。神经元样肾上腺髓质细胞合成和储存GDNF可能在肾上腺功能和/或维持支配肾上腺髓质的脊髓神经元中发挥作用。我们发现，单侧肾上腺髓质切除会导致T7-T10段脊髓中间外侧柱(IML)内所有投射到肾上腺髓质的交感节前神经元变性。原位杂交显示间质细胞表达糖基磷脂酰肌醇连接的α受体1和c-Ret受体，这两种受体是胶质细胞源性神经营养因子信号转导所必需的。转化生长因子-β(转化生长因子-β)受体II免疫反应阳性。4周后，将重组人1μg明胶海绵植入去髓肾上腺，可挽救所有投射至肾上腺髓质的节前神经元。细胞色素c作为对照蛋白不起作用。中和抗体可识别所有三种转化生长因子-β亚型，但不能识别胶质细胞源性神经营养因子，从而阻止神经营养因子的保护作用。提示内源性转化生长因子-β的存在是胶质细胞源性神经营养因子发挥神经营养作用所必需的。我们的数据表明，GDNF有能力保护一组自主神经脊髓神经元免受靶细胞死亡的影响。此外，我们的结果首次表明，先前报道的转化生长因子-β在体外允许神经营养因子的营养作用的要求(Krieglstein等人，1998年)也适用于体内的情况。
Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for several populations of CNS and peripheral neurons. Synthesis and storage of GDNF by the neuron-like adrenal medullary cells suggest roles in adrenal functions and/or in the maintenance of spinal cord neurons that innervate the adrenal medulla. We show that unilateral adrenomedullectomy causes degeneration of all sympathetic preganglionic neurons within the intermediolateral column (IML) of spinal cord segments T7–T10 that project to the adrenal medulla. In situ hybridization revealed that IML neurons express the glycosylphosphatidylinositol-linked α receptor 1 and c-Ret receptors, which are essential for GDNF signaling. IML neurons also display immunoreactivity for transforming growth factor-β (TGF-β) receptor II. Administration of GDNF (recombinant human, 1 μg) in Gelfoam implanted into the medullectomized adrenal gland rescued all Fluoro-Gold-labeled preganglionic neurons projecting to the adrenal medulla after four weeks. Cytochrome c applied as a control protein was not effective. The protective effect of GDNF was prevented by co-administration to the Gelfoam of neutralizing antibodies recognizing all three TGF-β isoforms but not GDNF. This suggests that the presence of endogenous TGF-β was essential for permitting a neurotrophic effect of GDNF. Our data indicate that GDNF has a capacity to protect a population of autonomic spinal cord neurons from target-deprived cell death. Furthermore, our results demonstrate for the first time that the previously reported requirement of TGF-β for permitting trophic actions of GDNF in vitro (Krieglstein et al., 1998) also applies to the in vivo situation.