MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression.
MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression.
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DOI：
10.1038/tp.2015.11
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发表时间：
2015-02-17
影响因子：
6.8
通讯作者：
Mechawar N
中科院分区：
文献类型：
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作者：
Maheu M;Lopez JP;Crapper L;Davoli MA;Turecki G;Mechawar N
尽管多项研究报道抑郁症患者外周胶质细胞源性神经营养因子（GDNF）减少，但在这种情况下大脑GDNF信号传导尚未得到研究。在这里，我们报告了GDNF家族受体α 1（GFRA 1）mRNA表达的亚型特异性降低，导致抑郁受试者基底外侧杏仁核（BLA）样本中GFRα1a蛋白水平降低。GFRα1a的下调与microRNA（包括miR-511）的表达增加相关，预测miR-511与编码GFRα1a的含长3'非翻译区（3'-UTR）的转录物（GFRA 1-L）结合。用miR-511模拟物转染人神经祖细胞（NPC）足以抑制GFRA 1-L/GFRα1a而不改变GFRα1b，并导致立即早期基因活性的途径特异性变化。出乎意料的是，GFRα1a敲低并没有减少NPC对GDNF的反应。相反，它大大增强了丝裂原活化蛋白激酶信号传导。这种效应似乎是由GDNF/可溶性GFRα1/神经细胞粘附分子结合介导的，并且用对照的可溶性GFRα1a/GFRα1b含量替代miR-511转染的NPC的可溶性GFRα1a/GFRα1b含量拯救信号传导。鉴于先前的报告表明GFRα1b可以抑制GFRα 1a诱导的神经可塑性，我们还评估了GFRα1与人BLA中双皮质素（DCX;一种增生标志物）之间的相关性。尽管对照组显示GFRα 1 a和B亚型的协调表达，并且这些亚型与DCX呈正相关，但在抑郁受试者中观察到的唯一显著相关性是GFRα 1 B与DCX之间的强烈负相关性。综上所述，这些结果表明，microRNA介导的GFRα1a降低在抑郁症中改变了GDNF信号转导的质量，而不是数量。他们还表明，中枢GDNF信号转导可能是抗抑郁治疗的一个新靶点。
Although multiple studies have reported that peripheral glial cell line-derived neurotrophic factor (GDNF) is reduced in depression, cerebral GDNF signalling has yet to be examined in this condition. Here, we report an isoform-specific decrease in GDNF family receptor alpha 1 (GFRA1) mRNA expression, resulting in lowered GFRα1a protein levels in basolateral amygdala (BLA) samples from depressed subjects. Downregulation of GFRα1a was associated with increased expression of microRNAs, including miR-511, predicted to bind to long 3' untranslated region (3'-UTR)-containing transcripts (GFRA1-L) coding for GFRα1a. Transfection of human neural progenitor cells (NPCs) with a miR-511 mimic was sufficient to repress GFRA1-L/GFRα1a without altering GFRα1b, and resulted in pathway-specific changes in immediate early gene activity. Unexpectedly, GFRα1a knockdown did not reduce NPC responses to GDNF. Rather, it greatly enhanced mitogen-activated protein kinase signalling. This effect appeared to be mediated by GDNF/soluble GFRα1/neural cell adhesion molecule binding, and substituting the soluble GFRα1a/GFRα1b content of miR-511-transfected NPCs with that of controls rescued signalling. In light of previous reports suggesting that GFRα1b can inhibit GFRα1a-induced neuroplasticity, we also assessed the association between GFRα1 and doublecortin (DCX; a hyperplastic marker) in human BLA. Although controls displayed coordinated expression of GFRα1a and b isoforms and these correlated positively with DCX, the only significant association observed among depressed subjects was a strongly negative correlation between GFRα1b and DCX. Taken together, these results suggest that microRNA-mediated reductions of GFRα1a in depression change the quality, rather than the quantity, of GDNF signalling. They also suggest that central GDNF signalling may represent a novel target for antidepressant treatment.