FMRP-Mediated Axonal Delivery of miR-181d Regulates Axon Elongation by Locally Targeting Map1b and Calm1

• Published in: Cell reports (Cambridge) 2015-12, Vol.13 (12), p.2794-2807
• Main Authors: Wang, Bin, Pan, Lin, Wei, Manyi, Wang, Qiong, Liu, Wen-Wen, Wang, Nuoxin, Jiang, Xing-Yu, Zhang, Xu, Bao, Lan
• Format: Article
• Language: English
• Subjects: Animals; Axons - metabolism; Calmodulin - genetics; Calmodulin - metabolism; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Mice; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Transfection
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.11.057

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 Fmr1I304N 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. [Display omitted] •Axon-enriched miR-181d regulates axon elongation by targeting axonal Map1b and Calm1•FMRP mediates axon delivery of miR-181d, Map1b, and Calm1•NGF triggers Map1b and Calm1 release from FMRP and miR-181d granules in axons•FMRP and miR-181d mediate NGF-induced axon elongation by translational regulation Wang et al. find that axon-enriched miR-181d regulates axon elongation by targeting axonal Map1b and Calm1 in primary sensory neurons. FMRP mediates delivery of miR-181d and its targets to the axon. NGF triggers Map1b and Calm1 release from FMRP and miR-181d-repressing granules in axons, controlling mRNA translation locally to induce axon elongation.