MicroRNA dysregulation following spinal cord contusion: implications for neural plasticity and repair

• Published in: Neuroscience Vol. 186; pp. 146 - 160
• Main Authors: Strickland, E.R, Hook, M.A, Balaraman, S, Huie, J.R, Grau, J.W, Miranda, R.C
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 14.07.2011; Elsevier
• Subjects: Animals; Biological and medical sciences; cell cycle failure; Disease Models, Animal; dysregulation; Fundamental and applied biological sciences. Psychology; Male; microRNA; MicroRNAs - antagonists & inhibitors; MicroRNAs - biosynthesis; MicroRNAs - genetics; Nerve Regeneration - genetics; Neurology; neuronal plasticity; Neuronal Plasticity - genetics; Rats; Rats, Sprague-Dawley; secondary SCI; Spinal Cord - metabolism; spinal cord contusion; Spinal Cord Injuries - genetics; Spinal Cord Injuries - metabolism; Vertebrates: nervous system and sense organs; microRNAs; BBB; miRNAs; Δ cycle threshold; ΔCT; CNS; quantitative reverse transcription; SOX2; analysis of variance; ANOVA; FDR; secondary SCI; interleukin; spinal cord injury; cell cycle failure; IL; Basso, Beattie, and Bresnahan; qRT-PCR; dysregulation; RE1-silencing transcription factor; small nucleolar RNA, C/D box 2; false-discovery rate; central nervous system; GFAP; neuronal plasticity; REST; spinal cord contusion; sex determining region Y-box 2; SCI; microRNA; glial fibrillary acidic protein; SNORD2; Spinal cord; Central nervous system; Micro RNA; Gene silencing; Cell cycle; Plasticity; Repair
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2011.03.063

Abstract Spinal cord injury (SCI) is medically and socioeconomically debilitating. Currently, there is a paucity of effective therapies that promote regeneration at the injury site, and limited understanding of mechanisms that can be utilized to therapeutically manipulate spinal cord plasticity. MicroRNAs (miRNAs) constitute novel targets for therapeutic intervention to promote repair and regeneration. Microarray comparisons of the injury sites of contused and sham rat spinal cords, harvested 4 and 14 days following SCI, showed that 32 miRNAs, including miR124, miR129, and miR1, were significantly down-regulated, whereas SNORD2, a translation-initiation factor, was induced. Additionally, three miRNAs including miR21 were significantly induced, indicating adaptive induction of an anti-apoptotic response in the injured cord. Validation of miRNA expression by qRT-PCR and in situ hybridization assays revealed that the influence of SCI on miRNA expression persists up to 14 days and expands both anteriorly and caudally beyond the lesion site. Specifically, changes in miR129-2 and miR146a expression significantly explained the variability in initial injury severity, suggesting that these specific miRNAs may serve as biomarkers and therapeutic targets for SCI. Moreover, the pattern of miRNA changes coincided spatially and temporally with the appearance of SOX2, nestin, and REST immunoreactivity, suggesting that aberrant expression of these miRNAs may not only reflect the emergence of stem cell niches, but also the reemergence in surviving neurons of a pre-neuronal phenotype. Finally, bioinformatics analysis of validated miRNA-targeted genes indicates that miRNA dysregulation may explain apoptosis susceptibility and aberrant cell cycle associated with a loss of neuronal identity, which underlies the pathogenesis of secondary SCI.