Spinal cord injury (SCI) can cause loss of sensory and motor function below the level of injury, posing a serious threat to human health and quality of life. One significant characteristic feature of pathological changes following injury in the nervous system is demyelination, which partially contributes to the long-term deficits in neural function after injury. The remyelination in the central nervous system (CNS) is mainly mediated by oligodendrocyte progenitor cells (OPCs). Numerous complex intracellular signaling and transcriptional factors regulate the differentiation process from OPCs to mature oligodendrocytes (OLs) and myelination. Studies have shown the importance of microRNA (miRNA) in regulating OPC functions. In this review, we focus on the demyelination and remyelination after SCI, and summarize the progress of miRNAs on OPC functions and remyelination, which might provide a potential therapeutic target for SCI treatments.
Increasing the intrinsic regeneration potential of neurons is the key to promote axon regeneration and repair of nerve injury. Therefore, identifying the molecular switches that respond to nerve injury may play critical role in improving intrinsic regeneration ability. The mechanisms by which injury unlocks the intrinsic axonal growth competence of mature neurons are not well understood. The present study identified the key regulatory genes after sciatic nerve crush injury by RNA sequencing (RNA-Seq) and found that the hub gene Vav1 was highly expressed at both early response and regenerative stages of sciatic nerve injury. Furthermore, Vav1 was required for axon regeneration of dorsal root ganglia (DRG) neurons and functional recovery. Krüppel-like factor 2 (Klf2) was induced by retrograde Ca2+ signaling from injured axons and could directly promote Vav1 transcription in adult DRG neurons. The increased Vav1 then promoted axon regeneration by activating Rac1 GTPase independent of its tyrosine phosphorylation. Collectively, these findings break through previous limited cognition of Vav1, and first reveal a crucial role of Vav1 as a molecular switch in response to axonal injury for promoting axon regeneration, which might further serve as a novel molecular therapeutic target for clinical nerve injury repair.
Nerve injuries are a common clinical problem and cause inconvenience in daily life. It is of great importance to get a full understanding of the biological processes and molecular mechanisms underlying nerve injury to find and target specific molecules in nerve regeneration. Numerous studies have shown that noncoding RNAs (ncRNAs) participate in diverse biological processes and diseases. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are two major groups of ncRNAs, which attract growing attention. The expression of lncRNAs and circRNAs are altered following nerve injury and are associated with nerve regeneration. This review will give a brief introduction of the origins, characteristics and classifications of lncRNAs and circRNAs. We then summarize the current studies on lncRNAs and circRNAs following peripheral nerve injury and spinal cord injury. Typical lncRNAs and circRNAs are introduced to illustrate the diverse molecular mechanisms. In addition, we also discuss some issues to be addressed in future investigations on lncRNAs and circRNAs.
Peripheral nerve injury is a common clinical problem. Nerve growth factor (NGF) promotes peripheral nerve regeneration, but its clinical applications are limited by several constraints. In this study, we found that the time-dependent expression profiles of eight let-7 family members in the injured nerve after sciatic nerve injury were roughly similar to each other. Let-7 microRNAs (miRNAs) significantly reduced cell proliferation and migration of primary Schwann cells (SCs) by directly targeting NGF and suppressing its protein translation. Following sciatic nerve injury, the temporal change in let-7 miRNA expression was negatively correlated with that in NGF expression. Inhibition of let-7 miRNAs increased NGF secretion by primary cultured SCs and enhanced axonal outgrowth from a coculture of primary SCs and dorsal root gangalion neurons. In vivo tests indicated that let-7 inhibition promoted SCs migration and axon outgrowth within a regenerative microenvironment. In addition, the inhibitory effect of let-7 miRNAs on SCs apoptosis might serve as an early stress response to nerve injury, but this effect seemed to be not mediated through a NGF-dependent pathway. Collectively, our results provide a new insight into let-7 miRNA regulation of peripheral nerve regeneration and suggest a potential therapy for repair of peripheral nerve injury. Peripheral nerve injury is a common clinical problem. Nerve growth factor (NGF) promotes peripheral nerve regeneration, but its clinical applications are limited by several constraints. In this study, we found that the time-dependent expression profiles of eight let-7 family members in the injured nerve after sciatic nerve injury were roughly similar to each other. Let-7 microRNAs (miRNAs) significantly reduced cell proliferation and migration of primary Schwann cells (SCs) by directly targeting NGF and suppressing its protein translation. Following sciatic nerve injury, the temporal change in let-7 miRNA expression was negatively correlated with that in NGF expression. Inhibition of let-7 miRNAs increased NGF secretion by primary cultured SCs and enhanced axonal outgrowth from a coculture of primary SCs and dorsal root gangalion neurons. In vivo tests indicated that let-7 inhibition promoted SCs migration and axon outgrowth within a regenerative microenvironment. In addition, the inhibitory effect of let-7 miRNAs on SCs apoptosis might serve as an early stress response to nerve injury, but this effect seemed to be not mediated through a NGF-dependent pathway. Collectively, our results provide a new insight into let-7 miRNA regulation of peripheral nerve regeneration and suggest a potential therapy for repair of peripheral nerve injury.
The intrinsic regeneration capacity of dorsal root ganglion (DRG) neurons can be activated after sciatic nerve injury, and peripheral nerve regeneration is a complex process regulated by multiple molecular responses and signaling pathways. Long non-coding RNAs (lncRNAs) are RNA transcripts > 200 nucleotides in length without protein-coding potential. They regulate gene expression at epigenetic, transcriptional and post-transcriptional levels, and are thus involved in many biological processes and human diseases. However, the role and mechanisms of lncRNAs in regulating the responses of DRG neurons to sciatic nerve injury are not fully investigated. We have previously analysed the expression profiles of lncRNAs and mRNAs in L4-6 DRGs, following rat sciatic nerve transection, by microarray analysis, and constructed a coexpression network of dysregulated lncRNAs and coding genes. In this study, one of these dysregulated lncRNAs, uc.217, was chosen for detailed examination of its expression changes and regulative functions in regenerative DRG neuronal outgrowth. Quantitative real-time PCR and in situ hybridisation confirmed that the expression of uc.217 was down-regulated in DRG neurons after sciatic nerve injury. Silencing of uc.217 expression by small interfering RNA could significantly promote neurite outgrowth in cultured DRG neurons. Moreover, bioinformatic analysis and experimental validation were performed to identify several potential targets of uc.217, which were involved in the regulation of DRG neuron outgrowth. Collectively, our results suggested that a new lncRNA, uc.217, played an important regulative role in peripheral nerve regeneration.
Abstract Background: Dickkopf-1 (DKK1), a secreted protein, is known as a negative regulator of the Wnt signaling pathway, which has been implicated in the development of several types of cancers. Clinical significance of serum DKK1 in lung cancer remains to be determined. Methods: A novel time-resolved immunofluorometric assay was developed. By use of this method, we investigated the serum concentrations of DKK1 in 592 patients with malignancies, 72 patients with benign lung disease, and 120 healthy controls. Serum cytokeratin 19 fragment and neuron-specific enolase values were obtained. Results: Serum DKK1 concentrations were significantly higher in patients with lung cancer than in patients with other malignant tumors or benign lung diseases and healthy controls. Serum concentrations of DKK1 were decreased significantly in groups of patients with gastric cancer, colorectal cancer, ovarian cancer, and cervical adenocarcinoma compared with healthy controls. Application of both DKK1 and cytokeratin 19 fragment increased sensitivity, correctly identifying 89.6% of the non–small cell lung cancer patients as positive. The use of both DKK1 and neuron-specific enolase increased sensitivity to detect small cell lung cancer to 86.2%. DKK1 concentrations increased with stage, tumor class, and presence of lymph node and distant metastases, regardless of histology and patient age and sex. Patients with a DKK1 concentration of 22.6 μg/L or higher had a statistically significantly diminished survival compared with patients whose DKK1 values were lower. Conclusions: DKK1 was preferentially expressed in lung cancer. Increasing concentrations of DKK1were significantly associated with tumor progression and decreased survival in patients with lung cancer. .
In contrast to the adult mammalian central nervous system (CNS), the neurons in the peripheral nervous system (PNS) can regenerate their axons. However, the underlying mechanism dictating the regeneration program after PNS injuries remains poorly understood. Combining chemical inhibitor screening with gain- and loss-of-function analyses, we identified p90 ribosomal S6 kinase 1 (RSK1) as a crucial regulator of axon regeneration in dorsal root ganglion (DRG) neurons after sciatic nerve injury (SNI). Mechanistically, RSK1 was found to preferentially regulate the synthesis of regeneration-related proteins using ribosomal profiling. Interestingly, RSK1 expression was up-regulated in injured DRG neurons, but not retinal ganglion cells (RGCs). Additionally, RSK1 overexpression enhanced phosphatase and tensin homolog (PTEN) deletion-induced axon regeneration in RGCs in the adult CNS. Our findings reveal a critical mechanism in inducing protein synthesis that promotes axon regeneration and further suggest RSK1 as a possible therapeutic target for neuronal injury repair.
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