Rihan Khalil, Antoine Etienne, Maurin Thomas, Bardoni Barbara, Bordonné Rémy, Soret Johann, Rage Florence
IGMM, CNRS, Université Montpellier, Montpellier, France.
Institut de Pharmacologie Moléculaire et Cellulaire, Physiopathologie du Retard Mental, 06560 Valbonne, France.
RNA. 2017 Jun;23(6):899-909. doi: 10.1261/rna.056788.116. Epub 2017 Mar 3.
Spinal muscular atrophy (SMA) is caused by mutations and/or deletions of the survival motor neuron gene (). Besides its function in the biogenesis of spliceosomal snRNPs, SMN might possess a motor neuron specific role and could function in the transport of axonal mRNAs and in the modulation of local protein translation. Accordingly, SMN colocalizes with axonal mRNAs of differentiated NSC-34 motor neuron-like cells. We recently showed that SMN depletion gives rise to a decrease in the axonal transport of the mRNAs encoding Annexin A2 (Anxa2). In this work, we have characterized the structural features of the Anxa2 mRNA required for its axonal targeting by SMN. We found that a G-rich motif located near the 3'UTR is essential for axonal localization of the Anxa2 transcript. We also show that mutations in the motif sequence abolish targeting of Anxa2 reporter mRNAs in axon-like structures of differentiated NSC-34 cells. Finally, localization of both wild-type and mutated Anxa2 reporters is restricted to the cell body in SMN-depleted cells. Altogether, our studies show that this G-motif represents a novel and essential determinant for axonal localization of the Anxa2 mRNA mediated by the SMN complex.
脊髓性肌萎缩症（SMA）是由存活运动神经元基因的突变和/或缺失引起的。除了在剪接体snRNP生物合成中的功能外，SMN可能具有运动神经元特异性作用，并可能在轴突mRNA运输和局部蛋白质翻译调节中发挥作用。因此，SMN与分化的NSC-34运动神经元样细胞的轴突mRNA共定位。我们最近发现，SMN缺失会导致编码膜联蛋白A2（Anxa2）的mRNA的轴突运输减少。在这项工作中，我们已经确定了SMN将Anxa2 mRNA靶向轴突所需的结构特征。我们发现位于3'UTR附近的富含G的基序对于Anxa2转录本的轴突定位至关重要。我们还表明，基序序列中的突变消除了Anxa2报告基因mRNA在分化的NSC-34细胞的轴突样结构中的靶向作用。最后，在SMN缺失的细胞中，野生型和突变型Anxa2报告基因的定位都局限于细胞体。总之，我们的研究表明，这个G基序代表了由SMN复合物介导的Anxa2 mRNA轴突定位的一个新的关键决定因素。
