A new cis-acting motif is required for the axonal SMN-dependent Anxa2 mRNA localization

Abstract

Spinal muscular atrophy (SMA) is caused by mutations and/or deletions of the survival motor neuron gene (SMN1). 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.

Dynamic m6A modification regulates local translation of mRNA in axons

“…Local translation can be regulated by various cis -elements in axonal mRNAs. For example, some cis -acting motifs in axonal mRNAs are required for axonal transport and targeting of mRNA ( 62 , 63 ). miRNA target sequences in axonal mRNA can recruit miRNA such as miR-132, miR-181d and miR-182, and regulate local translation ( 64–66 ).…”

The Small-Molecule Flunarizine in Spinal Muscular Atrophy Patient Fibroblasts Impacts on the Gemin Components of the SMN Complex and TDP43, an RNA-Binding Protein Relevant to Motor Neuron Diseases

“…It is interesting to note that SMN deficiency in lymphoblasts derived from SMA patients inhibits the splicing events mediated by the minor spliceosome (Boulisfane et al, 2011). Besides its role in snRNP biology and pre-mRNA splicing, SMN and Gemins complexes localize in dendrites and axons regulating axonal transport and local translation of specific mRNAs including those encoding for β-actin, Gap43, Anxa2, and Nrn1 proteins (Jablonka et al, 2006;Akten et al, 2011;Fallini et al, 2016;Rihan et al, 2017;Khalil et al, 2018).…”

The Important Role of Perituberal Tissue in Epileptic Patients with Tuberous Sclerosis Complex by the Transcriptome Analysis

“…APLNR encodes a member of the G protein-coupled receptor gene family, and ANXA2 encodes a member of the annexin family. In addition to their role in regulating tumor progression [ 33 , 34 ], APLNR is mainly involved in the neuroactive ligand-receptor interaction and vascular development [ 35 , 36 ], while ANXA2 mainly participates in the modulation of depressive behavior and signal transduction pathways [ 37 , 38 ]. CD44 encodes a cell-surface glycoprotein and affects the cell-cell interactions, cell adhesion, and migration, leading to a low survival in high-grade neuroblastoma, as well as synaptic remodeling and epileptogenesis [ 39 – 41 ].…”