State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
National Center of Nanoscience and Technology, Beijing 100190, China.
Cell Rep. 2015 Dec 29;13(12):2794-807. doi: 10.1016/j.celrep.2015.11.057. Epub 2015 Dec 17.
Subcellular targeting and local translation of mRNAs are critical for axon development. However, the precise local control of mRNA translation requires investigation. We report that the Fmr1-encoded protein, FMRP-mediated axonal delivery of miR-181d negatively regulates axon elongation by locally targeting the transcripts of MAP1B (Map1b) and calmodulin (Calm1) in primary sensory neurons. miR-181d affected the local synthesis of MAP1B and calmodulin in axons. FMRP was associated with miR-181d, Map1b, and Calm1. Both FMRP deficiency in Fmr1(I304N) mice and Fmr1 knockdown impeded the axonal delivery of miR-181d, Map1b, and Calm1 and reduced the protein levels of MAP1B and calmodulin in axons. Furthermore, nerve growth factor (NGF) induced Map1b and Calm1 release from FMRP and miR-181d-repressing granules, thereby promoting axon elongation. Both miR-181d overexpression and FMRP knockdown impaired NGF-induced axon elongation. Our study reveals a mechanism for the local regulation of translation by miR-181d and FMRP during axon development.
mRNA 的亚细胞靶向和局部翻译对轴突发育至关重要。然而，mRNA 翻译的精确局部控制需要进一步研究。我们报告称，Fmr1 编码的蛋白 FMRP 通过介导 miR-181d 在初级感觉神经元中的轴突运输，负调控轴突伸长，其作用机制是靶向 MAP1B（Map1b）和钙调蛋白（Calm1）的转录本。miR-181d 影响 MAP1B 和钙调蛋白在轴突中的局部合成。FMRP 与 miR-181d、Map1b 和 Calm1 相关。Fmr1(I304N) 小鼠中 FMRP 的缺乏和 Fmr1 的敲低均阻碍了 miR-181d、Map1b 和 Calm1 的轴突运输，并降低了 MAP1B 和钙调蛋白在轴突中的蛋白水平。此外，神经生长因子（NGF）诱导 Map1b 和 Calm1 从 FMRP 和 miR-181d 抑制颗粒中释放，从而促进轴突伸长。miR-181d 的过表达和 FMRP 的敲低均损害了 NGF 诱导的轴突伸长。本研究揭示了在轴突发育过程中，miR-181d 和 FMRP 通过调节翻译的局部机制。
