Silencing of miR20a is crucial for Ngn1-mediated neuroprotection in injured spinal cord.
ABSTRACT MicroRNAs (miRNAs) compose a relatively new discipline in biomedical research, and many physiological processes in disease have been associated with changes in miRNA expression. Several studies report that miRNAs participate in biological processes such as the control of secondary injury in several disease models. Recently, we identified novel miRNAs that were abnormally up-regulated in a traumatic spinal cord injury (SCI). In the current study, we focused on miR20a, which causes continuing motor neuron degeneration when overexpressed in SCI lesions. Blocking miR20a in SCI animals led to neural cell survival and eventual neurogenesis with rescued expression of the key target gene, neurogenin 1 (Ngn1). Infusion of siNgn1 resulted in functional deficit in the hindlimbs caused by aggressive secondary injury and actively enhanced the inflammation involved in secondary injury progression. The events involving miR20a underlie motor neuron and myelin destruction and pathophysiology and ultimately block regeneration in injured spinal cords. Inhibition of miR20a expression effectively induced definitive motor neuron survival and neurogenesis, and SCI animals showed improved functional deficit. In this study, we showed that abnormal expression of miR20a induces secondary injury, which suggests that miR20a could be a potential target for therapeutic intervention following SCI.
- [Show abstract] [Hide abstract]
ABSTRACT: MicroRNAs (miRNAs) are small, endogenous, non-coding RNA molecules that function as post-transcriptional regulators of gene expression by imperfect base-pairing with the 3'-untranslated regions of their target mRNAs. Altered expression of numerous miRNAs has been shown to be extensively involved in the pathogenesis of various diseases and cancers. Additionally, the specific expression of miRNAs in the nervous system has indicated that miRNAs are critical for the occurrence and development of neurological diseases. Increasing evidence has shown that specific miRNAs target the expression of particular proteins that are significant in the disease pathogenesis. Therefore, miRNA-mediated regulation may be important in the occurrence and development of neurological diseases and may function as a novel biomarker and tool for clinical therapy. In the present study, the significance of miRNAs is reviewed in a number of neurological disorders and the possibility of their use in therapeutic interventions is evaluated.Biomedical reports. 09/2014; 2(5):611-619.
- [Show abstract] [Hide abstract]
ABSTRACT: Trauma to the spinal cord causes permanent disability to more than 180,000 people every year worldwide. The initial mechanical damage triggers a complex set of secondary events involving the neural, vascular, and immune systems that largely determine the functional outcome of the spinal cord injury (SCI). Cellular and biochemical mechanisms responsible for this secondary injury largely depend on activation and inactivation of specific gene programs. Recent studies indicate that microRNAs function as gene expression switches in key processes of the SCI. Microarray data from rodent contusion models reveal that SCI induces changes in the global microRNA expression patterns. Variations in microRNA abundance largely result from alterations in the expression of the cells at the damaged spinal cord. However, microRNA expression levels after SCI are also influenced by the infiltration of immune cells to the injury site and the death and migration of specific neural cells after injury. Evidences on the role of microRNAs in the SCI pathophysiology have come from different sources. Bioinformatic analysis of microarray data has been used to identify specific variations in microRNA expression underlying transcriptional changes in target genes, which are involved in key processes in the SCI. Direct evidences on the role of microRNAs in SCI are scarcer, although recent studies have identified several microRNAs (miR-21, miR-486, miR-20) involved in key mechanisms of the SCI such as cell death or astrogliosis, among others. From a clinical perspective, different evidences make clear that microRNAs can be potent therapeutic tools to manipulate cell state and molecular processes in order to enhance functional recovery. The present article reviews the actual knowledge on how injury affects microRNA expression and the meaning of these changes in the SCI pathophysiology, to finally explore the clinical potential of microRNAs in the SCI.Frontiers in Cellular Neuroscience 01/2014; 8:53. · 4.47 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Neuroblastoma is an embryonic tumour of the sympathetic nervous system and is one of the most common cancers in childhood. A high differentiation stage has been associated with a favourable outcome; however, the mechanisms governing neuroblastoma cell differentiation are not completely understood. The MYCN gene is considered the hallmark of neuroblastoma. Even though it has been reported that MYCN has a role during embryonic development, it is needed its decrease so that differentiation can be completed. We aimed to better define the role of MYCN in the differentiation processes, particularly during the early stages. Considering the ability of MYCN to regulate non-coding RNAs, our hypothesis was that N-Myc protein might be necessary to activate differentiation (mimicking embryonic development events) by regulating miRNAs critical for this process. We show that MYCN expression increased in embryonic cortical neural precursor cells at an early stage after differentiation induction. To investigate our hypothesis, we used human neuroblastoma cell lines. In LAN-5 neuroblastoma cells, MYCN was upregulated after 2 days of differentiation induction before its expected downregulation. Positive modulation of various differentiation markers was associated with the increased MYCN expression. Similarly, MYCN silencing inhibited such differentiation, leading to negative modulation of various differentiation markers. Furthermore, MYCN gene overexpression in the poorly differentiating neuroblastoma cell line SK-N-AS restored the ability of such cells to differentiate. We identified three key miRNAs, which could regulate the onset of differentiation programme in the neuroblastoma cells in which we modulated MYCN. Interestingly, these effects were accompanied by changes in the apoptotic compartment evaluated both as expression of apoptosis-related genes and as fraction of apoptotic cells. Therefore, our idea is that MYCN is necessary during the activation of neuroblastoma differentiation to induce apoptosis in cells that are not committed to differentiate.Cell Death & Disease 01/2014; 5:e1081. · 6.04 Impact Factor