Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure.
Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure.
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DOI：
10.1126/science.aad2509
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发表时间：
2015-12-18
期刊：
影响因子：
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通讯作者：
Pfaff SL
中科院分区：
文献类型：
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作者：
Amin ND;Bai G;Klug JR;Bonanomi D;Pankratz MT;Gifford WD;Hinckley CA;Sternfeld MJ;Driscoll SP;Dominguez B;Lee KF;Jin X;Pfaff SL
微RNA（miRNA）代谢功能障碍被认为是影响运动神经元的疾病的基础。一种miRNA，miR-218，在发育和成熟的运动神经元中大量且选择性地表达。在这里，我们发现，缺乏miR-218的突变小鼠死亡，并表现出神经肌肉接头缺陷，运动神经元过度兴奋和进行性运动神经元细胞丢失，所有这些都是运动神经元疾病的标志，如肌萎缩性侧索硬化症和脊髓性肌萎缩症。基因分析显示，miR-218适度抑制了神经元富集的数百个基因，但对单个神经元亚群没有特异性。因此，由miR-218靶向的信使RNA组（指定为target 218）定义了在运动神经元中选择性下调以防止神经肌肉衰竭和神经变性的神经元基因网络。
Dysfunction of microRNA (miRNA) metabolism is thought to underlie diseases affecting motoneurons. One miRNA, miR-218, is abundantly and selectively expressed by developing and mature motoneurons. Here we show that mutant mice lacking miR-218 die neonatally and exhibit neuromuscular junction defects, motoneuron hyperexcitability, and progressive motoneuron cell loss, all of which are hallmarks of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Gene profiling reveals that miR-218 modestly represses a cohort of hundreds of genes that are neuronally enriched but are not specific to a single neuron subpopulation. Thus, the set of messenger RNAs targeted by miR-218, designated target218, defines a neuronal gene network that is selectively tuned down in motoneurons to prevent neuromuscular failure and neurodegeneration.