Abstract
Following injury, dorsal root ganglion (DRG) neurons undergo transcriptional changes so as to adopt phenotypic changes that promote cell survival and axonal regeneration. Here we used a microarray approach to profile changes in a population of small noncoding RNAs known as microRNAs (miRNAs) in the L4 and L5 DRG following sciatic nerve transection. Results showed that 20 miRNA transcripts displayed a significant change in expression levels, with 8 miRNAs transcripts being altered by more than 1.5-fold. Using quantitative reverse transcription PCR, we demonstrated that one of these miRNAs, miR-21, was upregulated by 7-fold in the DRG at 7 days post-axotomy. In dissociated adult rat DRG neurons lentiviral vector-mediated overexpression of miR-21 promoted neurite outgrowth on a reduced laminin substrate. miR-21 directly downregulated expression of Sprouty2 protein, as confirmed by Western blot analysis and 3′ untranslated region (UTR) luciferase assays. Our data show that miR-21 is an axotomy-induced miRNA that enhances axon growth, and suggest that miRNAs are important players in regulating growth pathways following peripheral nerve injury.
Highlights
Sciatic nerve injury triggers gene expression changes in the dorsal root ganglion (DRG) of transected nerves and in the microenvironment of the nerve stumps
Statistical analyses revealed that 20 miRNA transcripts were differentially expressed in axotomised DRG compared to the non-axotomised contralateral DRG; with 8 being upregulated and 12 down-regulated
Sciatic nerve injury activates transcription factors such as c-Jun [25], ATF3 [26] and Stat3 [27], which in turn modulate gene expression and stimulate axon growth to reconnect with peripheral targets
Summary
Sciatic nerve injury triggers gene expression changes in the dorsal root ganglion (DRG) of transected nerves and in the microenvironment of the nerve stumps. A large number of genes and proteins were found to be regulated; these were diverse and distinct, comprising members of several classes such as neuropeptides, receptors, ion channels, signal transduction molecules, synaptic vesicle proteins, cell cytoskeletal components, extracellular matrices and inflammatory mediators. While these studies have provided an insight into the molecular changes that occur in the injured nerve and its environs, it is still unknown how these global changes are regulated in a coordinated fashion. Another possible mechanism of coordinated control can occur at the post-transcriptional level, for example regulation by microRNAs (miRNAs)
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