Abstract
Spinal cord injury (SCI) affects 6 million people worldwide with no available treatment. Despite research advances, the inherent poor regeneration potential of the central nervous system remains a major hurdle. Small RNAs (sRNAs) 19–33 nucleotides in length are a set of non-coding RNA molecules that regulate gene expression and have emerged as key players in regulating cellular events occurring after SCI. Here we profiled a class of sRNA known as microRNAs (miRNAs) following SCI in the cortex where the cell bodies of corticospinal motor neurons are located. We identified miR-7b-3p as a candidate target given its significant upregulation after SCI in vivo and we screened by miRWalk PTM the genes predicted to be targets of miR-7b-3p (among which we identified Wipf2, a gene regulating neurite extension). Moreover, 16 genes, involved in neural regeneration and potential miR-7b-3p targets, were found to be downregulated in the cortex following SCI. We also analysed miR-7b-3p function during cortical neuron development in vitro: we observed that the overexpression of miR-7b-3p was important (1) to maintain neurons in a more immature and, likely, plastic neuronal developmental phase and (2) to contrast the apoptotic pathway; however, in normal conditions it did not affect the Wipf2 expression. On the contrary, the overexpression of miR-7b-3p upon in vitro oxidative stress condition (mimicking the SCI environment) significantly reduced the expression level of Wipf2, as observed in vivo, confirming it as a direct miR-7b-3p target. Overall, these data suggest a dual role of miR-7b-3p: (i) the induction of a more plastic neuronal condition/phase, possibly at the expense of the axon growth, (ii) the neuroprotective role exerted through the inhibition of the apoptotic cascade. Increasing the miR-7b-3p levels in case of SCI could reactivate in adult neurons silenced developmental programmes, supporting at the same time the survival of the axotomised neurons.
Highlights
Around 6 million people worldwide live with a significant disability caused by traumatic spinal cord injury (SCI), which is associated with devastating social impact plus huge economic cost (Singh et al, 2014)
We did not detect degenerating cells by Fluoro-Jade C (FJC) staining in the sensorimotor cortex, whereas degenerating cells were markedly visible in the spinal cord of SCI mice (Supplementary Figure 2)
We investigated the miRNA profile in SCI in order to identify specific miRNAs involved in regeneration/plasticity
Summary
Around 6 million people worldwide live with a significant disability caused by traumatic spinal cord injury (SCI), which is associated with devastating social impact plus huge economic cost (Singh et al, 2014). Motor disabilities that follow SCI trauma are essentially due to axotomised corticospinal fibres [corticospinal motor neurons (CSMNs) whose cell body is located in the layer V of the cortex] that are unable to re-establish functional connections. No successful treatment is available for SCI patients several therapeutic interventions such as cell engraftment, 3D scaffolds and gene therapy are currently under investigation. These interventions aim to reduce glial scar formation and to promote neuronal regeneration (Assinck et al, 2017; Boido et al, 2019; Cofano et al, 2019; Zhang et al, 2019)
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