GDNF-Induced Osteopontin from Muller Glial Cells Promotes Photoreceptor Survival in the Pde6brd1 Mouse Model of Retinal Degeneration
GDNF-Induced Osteopontin from Muller Glial Cells Promotes Photoreceptor Survival in the Pde6brd1 Mouse Model of Retinal Degeneration
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DOI：
10.1002/glia.21155
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发表时间：
2011-05-01
期刊：
影响因子：
6.2
通讯作者：
Ueffing, Marius
中科院分区：
文献类型：
--
作者：
Del Rio, Patricia;Irmler, Martin;Ueffing, Marius
胶质细胞源性神经营养因子（GDNF）可增强多种神经元的存活，包括视网膜中的光感受器（PR）。然而，与大多数其他GDNF受体神经元相反，GDNF不直接对PR神经元发挥其神经保护活性，而是通过诱导视网膜Muller神经胶质（RMG）细胞中未知的神经营养因子的表达来间接传递。全基因组差异转录组分析的GDNF处理的小鼠视网膜显示30个GDNF诱导的转录本含有共6个基因编码的分泌分子。其中有（OPN），一种分泌型糖蛋白，在小鼠RMG中表达，并从培养的原代小鼠RMG中分泌。此外，GDNF治疗原发性RMG后，OPN分泌显著上调。为了验证OPN是否有资格作为PR的神经保护因子，我们评估了其对体外分离的PR以及视网膜变性1（Pde 6 b（rd 1））小鼠突变体的视网膜外植体的潜在神经营养活性。OPN以浓度依赖性方式对原代猪PR细胞产生显著的正存活效应，并诱导PI 3 K/Akt促存活通路的激活。此外，在来自Pde 6 b（rd 1）小鼠的视网膜外植体培养物中，OPN显著降低凋亡细胞的百分比至与在来自野生型小鼠的外植体中观察到的水平相当的水平，并且导致在长期视网膜外植体培养物中显著更多的PR存活。我们的研究结果表明，RMG衍生的OPN是一种新的候选蛋白，它将RMG的部分GDNF诱导的神经保护活性传递给PR细胞。(c)2011 Wiley-Liss，Inc.
Glial cell line-derived neurotrophic factor (GDNF) enhances the survival of a variety of neurons, including photoreceptors (PR) in the retina. In contrast to most other GDNF receptive neurons, GDNF does, however, not exert its neuroprotective activity directly on PR neurons but transmits it indirectly by inducing expression of yet unknown neurotrophic factors in retinal Muller glial (RMG) cells. Genome-wide differential transcriptome analyses of GDNF-treated mouse retinas revealed 30 GDNF-induced transcripts containing a total of six genes coding for secreted molecules. Among them was (OPN), a secreted glycoprotein which was expressed in mouse RMG and secreted from primary mouse RMG in culture. Furthermore, OPN secretion was significantly upregulated on GDNF treatment of primary RMG. To validate, whether OPN could qualify as a neuroprotective factor for PR, we evaluated its potential neurotrophic activity on isolated PR in vitro as well as on retinal explants from the retinal degeneration 1 (Pde6b(rd1)) mouse mutant. OPN exerted a significant, positive survival effect on primary porcine PR cells in a concentration-dependent manner and induced activation of PI3K/Akt pro-survival pathway. Moreover, in retinal explant cultures from Pde6b(rd1) mice, OPN significantly reduced the percentage of apoptotic cells to levels comparable with that observed in explants from wild-type mice and led to survival of significantly more PR in long-term retinal explant cultures. Our findings suggest that RMG-derived OPN is a novel candidate protein that transmits part of the GDNF-induced neuroprotective activity of RMG to PR cells. (c) 2011 Wiley-Liss, Inc.