The GDNF System Is Altered in Diverticular Disease - Implications for Pathogenesis.
The GDNF System Is Altered in Diverticular Disease - Implications for Pathogenesis.
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DOI：
10.1371/journal.pone.0066290
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wedel T
中科院分区：
文献类型：
--
作者：
Böttner M;Barrenschee M;Hellwig I;Harde J;Egberts JH;Becker T;Zorenkov D;Schäfer KH;Wedel T
缺乏胶质细胞源性神经营养因子(GDNF)会导致肠无神经节细胞增多症。我们最近证实，憩室病(DD)患者表现出神经节细胞减少症，提示神经营养因子缺乏。因此，我们筛选了DD时GDNF系统的mRNA表达模式，并检测了GDNF对培养的肠神经细胞的影响。检测DD患者(n = 2 1)和正常对照组(n = 2 0)结肠组织中胶质细胞源性神经营养因子及其受体GFRα1和RET的基因表达水平。为了确定GDNF及其受体的组织来源，分别对人肌间神经节和肠肌层的激光显微解剖(LMD)标本进行了定量聚合酶链式反应分析。此外，还观察了GDNF对培养的肠神经细胞(受体表达、神经元分化和可塑性)的影响。DD患者固有肌中GDNF及其受体的mRNA表达明显下调。LMD标本在环肌层和纵肌层均有GDNF高表达，肌间神经节也有GDNF受体表达。GDNF作用于培养的肠神经细胞，可增加其受体的mRNA表达，促进突触素mRNA和蛋白表达所揭示的神经元分化和可塑性。我们的结果表明，GDNF系统在DD中受到了损害。体外研究表明，GDNF增强其受体的表达，促进肠神经分化和可塑性。由于DD患者表现为神经节细胞缺乏症，我们认为DD患者的肠神经元丢失可能是由于缺乏GDNF系统介导的神经营养支持所致。
Absence of glial cell line-derived neurotrophic factor (GDNF) leads to intestinal aganglionosis. We recently demonstrated that patients with diverticular disease (DD) exhibit hypoganglionosis suggesting neurotrophic factor deprivation. Thus, we screened mRNA expression pattern of the GDNF system in DD and examined the effects of GDNF on cultured enteric neurons. Colonic specimens obtained from patients with DD (n = 21) and controls (n = 20) were assessed for mRNA expression levels of the GDNF system (GDNF, GDNF receptors GFRα1 and RET). To identify the tissue source of GDNF and its receptors, laser-microdissected (LMD) samples of human myenteric ganglia and intestinal muscle layers were analyzed separately by qPCR. Furthermore, the effects of GDNF treatment on cultured enteric neurons (receptor expression, neuronal differentiation and plasticity) were monitored. mRNA expression of GDNF and its receptors was significantly down-regulated in the muscularis propria of patients with DD. LMD samples revealed high expression of GDNF in circular and longitudinal muscle layers, whereas GDNF receptors were also expressed in myenteric ganglia. GDNF treatment of cultured enteric neurons increased mRNA expression of its receptors and promoted neuronal differentiation and plasticity revealed by synaptophysin mRNA and protein expression. Our results suggest that the GDNF system is compromised in DD. In vitro studies demonstrate that GDNF enhances expression of its receptors and promotes enteric neuronal differentiation and plasticity. Since patients with DD exhibit hypoganglionosis, we propose that the observed enteric neuronal loss in DD may be due to lacking neurotrophic support mediated by the GDNF system.
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