Medical Research Council Laboratory for Molecular and Cell Biology, University College London, London, UK.
Nat Neurosci. 2010 Mar;13(3):291-301. doi: 10.1038/nn.2486. Epub 2010 Jan 31.
mRNA localization is an evolutionary conserved mechanism that underlies the establishment of cellular polarity and specialized cell functions. To identify mRNAs localized in subcellular compartments of developing neurons, we took an original approach that combines compartmentalized cultures of rat sympathetic neurons and sequential analysis of gene expression (SAGE). Unexpectedly, the most abundant transcript in axons was mRNA for myo-inositol monophosphatase-1 (Impa1), a key enzyme that regulates the inositol cycle and the main target of lithium in neurons. A novel localization element within the 3' untranslated region of Impa1 mRNA specifically targeted Impa1 transcript to sympathetic neuron axons and regulated local IMPA1 translation in response to nerve growth factor (NGF). Selective silencing of IMPA1 synthesis in axons decreased nuclear CREB activation and induced axonal degeneration. These results provide insights into mRNA transport in axons and reveal a new NGF-responsive localization element that directs the targeting and local translation of an axonal transcript.
mRNA 定位是一种进化保守的机制，它是建立细胞极性和特化细胞功能的基础。为了鉴定定位于发育神经元亚细胞区室的 mRNAs，我们采用了一种结合大鼠交感神经元分区培养和基因表达顺序分析（SAGE）的独特方法。出乎意料的是，轴突中最丰富的转录本是肌醇单磷酸酶-1（Impa1）mRNA，它是调节肌醇循环的关键酶，也是神经元中锂的主要靶标。Impa1 mRNA 3'非翻译区中的一个新的定位元件特异性地将 Impa1 转录本靶向到交感神经元轴突中，并调节局部 IMPA1 翻译对神经生长因子（NGF）的反应。轴突中 IMPA1 合成的选择性沉默降低了核 CREB 激活并诱导轴突退化。这些结果深入了解了轴突中 mRNA 的运输，并揭示了一种新的 NGF 反应性定位元件，该元件指导轴突转录本的靶向和局部翻译。
