Genome-wide identification of mRNAs associated with the protein SMN whose depletion decreases their axonal localization

Rage, Florence; Boulisfane, Nawal; Rihan, Khalil; Neel, H. Bryan; Gostan, Thierry; Bertrand, Édouard; Bordonne, Rémy; Soret, Johann

doi:10.1261/rna.040204.113

Cited by 54 publications

(66 citation statements)

References 72 publications

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“…These studies suggest an involvement of SMN in the regulation of the assembly of ribonucleoproteins responsible for the transport, stability, and/or local translation of axonal mRNAs (Talbot and Davies 2008;Akten et al 2011;Fallini et al 2011;Hubers et al 2011). Consistent with this hypothesis, we recently identified numerous axonal mRNAs associated with the SMN complex in differentiated NSC-34 motor neuron-like cells using a genome-wide analysis (Rage et al 2013). We found also that axonal localization of some mRNAs is altered in SMN-depleted cells, indicating that SMN deficiency might indeed lead to the mislocalization of mRNPs required for axonal outgrowth and/or function.…”

Section: Introductionsupporting

confidence: 69%

“…In this work, we examined the transport of the mRNA encoding the mouse Annexin A2 (Anxa2) that we previously showed to be SMN-dependent in differentiated NSC-34 motor neuron-like cells (Rage et al 2013). Annexin A2 is a ubiquitous Ca 2+ -binding protein that is essential for actin-dependent vesicle transport and which has been shown to be a critical regulator of actin remodeling in the proximity of dynamic cellular membranes (Hayes et al 2006;Grieve et al 2012;Gabel et al 2015).…”

Section: Introductionmentioning

confidence: 99%

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

Rihan

Antoine

Maurin

et al. 2017

RNA

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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.

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Section: Introductionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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

Rihan

Antoine

Maurin

et al. 2017

RNA

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“…For example, ALS-causing mutations in the RNA-binding protein TDP-43 impairs axonal trafficking of mRNA granules to distal axons [41]. Similarly, reduced levels of survival of motor neuron (SMN) decrease axonal mRNA localization and human SMN1 mutations that alter the amount of functional protein are responsible for most SMA cases [42]. Reduced SMN levels, such as seen in SMA, cause increase expression of microRNA-138, which, in turn, leads to reduced local mammalian target of rapamycin synthesis and activity in axons [43].…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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Localized protein synthesis is a mechanism by which morphologically polarized cells react in a spatially confined and temporally acute manner to changes in their environment. During the development of the nervous system intra-axonal protein synthesis is crucial for the establishment of neuronal connections. In contrast, mature axons have long been considered as translationally inactive but upon nerve injury or under neurodegenerative conditions specific subsets of mRNAs are recruited into axons and locally translated. Intra-axonally synthesized proteins can have pathogenic or restorative and regenerative functions, and thus targeting the axonal translatome might have therapeutic value, for example in the treatment of spinal cord injury or Alzheimer's disease. In the case of Alzheimer's disease the local synthesis of the stress response transcription factor activating transcription factor 4 mediates the long-range retrograde spread of pathology across the brain, and inhibition of local Atf4 translation downstream of the integrated stress response might interfere with this spread. Several molecular tools and approaches have been developed to target specifically the axonal translatome by either overexposing proteins locally in axons or, conversely, knocking down selectively axonally localized mRNAs. Many questions about axonal translation remain to be answered, especially with regard to the mechanisms establishing specificity but, nevertheless, targeting the axonal translatome is a promising novel avenue to pursue in the development for future therapies for various neurological conditions.

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“…The studies identified about 400 RNA species potentially binding with axonal SMN. A further study found more than 1000 genes dysregulated in neurites of NSC-34 cells and smn-depleted primary mouse motor neurones [121][122][123]. Among these genes are a number involved in axonal outgrowth, synaptogenesis, neurogenesis and neurotransmitter release [121,122].…”

Section: Accepted Manuscriptmentioning

confidence: 97%

Spinal muscular atrophy: Factors that modulate motor neurone vulnerability

Simpson

Highley

et al. 2017

Neurobiology of Disease

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Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets. Keywords:Selective vulnerability, SMA, SMN, disease modifier, motor neurone disease ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T Highlights: Factors that influence vulnerability of motor neurons in SMA. SMA disease modification. Impact of surrounding cells on neuronal death. Precise molecular defects in SMA; mRNA splicing and miRNA interactions. Cytoskeletal stability and axonal transport effects.

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Genome-wide identification of mRNAs associated with the protein SMN whose depletion decreases their axonal localization

Cited by 54 publications

References 72 publications

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

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

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Spinal muscular atrophy: Factors that modulate motor neurone vulnerability

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