The Robert F. Furchgott Center for Neural and Behavioral Science, Department of Physiology and Pharmacology, State University of New York, Health Science Center at Brooklyn, USA.
J Cell Biol. 2011 Aug 8;194(3):441-57. doi: 10.1083/jcb.201010027. Epub 2011 Aug 1.
In neurons, regulation of gene expression occurs in part through translational control at the synapse. A fundamental requirement for such local control is the targeted delivery of select neuronal mRNAs and regulatory RNAs to distal dendritic sites. The nature of spatial RNA destination codes, and the mechanism by which they are interpreted for dendritic delivery, remain poorly understood. We find here that in a key dendritic RNA transport pathway (exemplified by BC1 RNA, a dendritic regulatory RNA, and protein kinase M ζ [PKMζ] mRNA, a dendritic mRNA), noncanonical purine•purine nucleotide interactions are functional determinants of RNA targeting motifs. These motifs are specifically recognized by heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2), a trans-acting factor required for dendritic delivery. Binding to hnRNP A2 and ensuing dendritic delivery are effectively competed by RNAs with CGG triplet repeat expansions. CGG repeats, when expanded in the 5' untranslated region of fragile X mental retardation 1 (FMR1) mRNA, cause fragile X-associated tremor/ataxia syndrome. The data suggest that cellular dysregulation observed in the presence of CGG repeat RNA may result from molecular competition in neuronal RNA transport pathways.
在神经元中，基因表达的调控部分是通过突触处的翻译控制来实现的。这种局部控制的一个基本要求是将特定的神经元 mRNA 和调节 RNA 靶向递送至远端树突部位。目前，对于这种空间 RNA 目标代码的性质，以及它们如何被解释用于树突递呈，人们仍知之甚少。我们在这里发现，在一个关键的树突 RNA 运输途径中（以 BC1 RNA，一种树突状调节 RNA 和蛋白激酶 M ζ [PKMζ] mRNA，一种树突状 mRNA 为例），非典型嘌呤•嘌呤核苷酸相互作用是 RNA 靶向基序的功能决定因素。这些基序被异质核核糖核蛋白 A2（hnRNP A2）特异性识别，hnRNP A2 是树突递呈所必需的反式作用因子。hnRNP A2 的结合和随后的树突递呈可被具有 CGG 三核苷酸重复扩展的 RNA 有效竞争。当 CGG 重复在脆性 X 智力低下 1（FMR1）mRNA 的 5'非翻译区扩展时，会导致脆性 X 相关震颤/共济失调综合征。数据表明，在 CGG 重复 RNA 存在的情况下观察到的细胞失调可能是由于神经元 RNA 运输途径中的分子竞争所致。
