Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains
Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains
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DOI：
10.1093/hmg/ddw381
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发表时间：
2017-01-01
影响因子：
3.5
通讯作者：
Fallon, Justin R.
中科院分区：
文献类型：
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作者：
Akins, Michael R.;Berk-Rauch, Hanna E.;Fallon, Justin R.
生长轴突中的局部mRNA翻译允许在响应外部刺激时快速和精确地调节蛋白质表达。然而，局部翻译在成熟中枢神经系统轴突中的作用尚不清楚。这种机制需要在电路集成的脑轴突中存在翻译机制和相关mrna。在这里，我们使用遗传、定量成像和超分辨率显微镜相结合的方法来显示哺乳动物大脑中的成熟轴突含有核糖体、翻译调节因子FMRP和FMRP mRNA靶点子集。这种轴突翻译机制与脆性X颗粒（FXGs）有关，它局限于脑回路的一个刻板子集中的轴突。FXGs和相关的轴突翻译机制存在于57岁的人类海马中。这种与fxg相关的轴突翻译机制存在于成年大鼠中，即使成年神经发生被阻断。相比之下，在小鼠中，这种机制仅在幼年海马轴突中观察到。这种不同的发育表达是海马特有的，因为小鼠和大鼠在成年嗅觉系统的成熟轴突中都表现出FXGs。在Fmr1缺失小鼠中进行的实验表明，FMRP调节轴突蛋白表达，但不是核糖体或其靶mrna轴突运输所必需的。轴突翻译机制是成年中枢神经系统神经元的一个特征。FMRP对这一机制的调节可以支持人类一生中的复杂行为。
Local mRNA translation in growing axons allows for rapid and precise regulation of protein expression in response to extrinsic stimuli. However, the role of local translation in mature CNS axons is unknown. Such a mechanism requires the presence of translational machinery and associated mRNAs in circuit-integrated brain axons. Here we use a combination of genetic, quantitative imaging and super-resolution microscopy approaches to show that mature axons in the mammalian brain contain ribosomes, the translational regulator FMRP and a subset of FMRP mRNA targets. This axonal translational machinery is associated with Fragile X granules (FXGs), which are restricted to axons in a stereotyped subset of brain circuits. FXGs and associated axonal translational machinery are present in hippocampus in humans as old as 57 years. This FXG-associated axonal translational machinery is present in adult rats, even when adult neurogenesis is blocked. In contrast, in mouse this machinery is only observed in juvenile hippocampal axons. This differential developmental expression was specific to the hippocampus, as both mice and rats exhibit FXGs in mature axons in the adult olfactory system. Experiments in Fmr1 null mice show that FMRP regulates axonal protein expression but is not required for axonal transport of ribosomes or its target mRNAs. Axonal translational machinery is thus a feature of adult CNS neurons. Regulation of this machinery by FMRP could support complex behaviours in humans throughout life.