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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >MicroRNAs modulate Schwann cell response to nerve injury by reinforcing transcriptional silencing of dedifferentiation-related genes.
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MicroRNAs modulate Schwann cell response to nerve injury by reinforcing transcriptional silencing of dedifferentiation-related genes.

机译：MicroRNA通过增强去分化相关基因的转录沉默来调节雪旺细胞对神经损伤的反应。

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In the peripheral nervous system, Schwann cells (SCs) surrounding damaged axons undergo an injury response that is driven by an intricate transcriptional program and is critical for nerve regeneration. To examine whether these injury-induced changes in SCs are also regulated posttranscriptionally by miRNAs, we performed miRNA expression profiling of mouse sciatic nerve distal segment after crush injury. We also characterized the SC injury response in mice containing SCs with disrupted miRNA processing due to loss of Dicer. We identified 87 miRNAs that were expressed in mouse adult peripheral nerve, 48 of which were dynamically regulated after nerve injury. Most of these injury-regulated SC miRNAs were computationally predicted to inhibit drivers of SC dedifferentiation/proliferation and thereby re-enforce the transcriptional program driving SC remyelination. SCs deficient in miRNAs manifested a delay in the transition between the distinct differentiation states required to support peripheral nerve regeneration. Among the miRNAs expressed in adult mouse SCs, miR-34a and miR-140 were identified as functional regulators of SC dedifferentiation/proliferation and remyelination, respectively. We found that miR-34a interacted with positive regulators of dedifferentiation and proliferation such as Notch1 and Ccnd1 to control cell cycle dynamics in SCs. miR-140 targeted the transcription factor Egr2, a master regulator of myelination, and modulated myelination in DRG/SC cocultures. Together, these results demonstrate that SC miRNAs are important modulators of the SC regenerative response after nerve damage.
机译：在周围神经系统中，受损轴突周围的雪旺细胞（SCs）受到损伤反应，该反应由复杂的转录程序驱动，对神经再生至关重要。为了检查这些损伤诱导的SCs的变化是否也由miRNA转录后调控，我们在挤压伤后对小鼠坐骨神经末梢进行了miRNA表达谱分析。我们还表征了含有Dicer缺失而导致miRNA加工中断的SC小鼠的SC损伤反应。我们鉴定了在小鼠成年末梢神经中表达的87个miRNA，其中48个在神经损伤后受到动态调节。这些受损伤调节的SC miRNA中的大多数已通过计算预测可抑制SC脱分化/增殖的驱动力，从而增强驱动SC重新髓鞘化的转录程序。缺乏miRNA的SC表现出支持周围神经再生所需的不同分化状态之间转换的延迟。在成年小鼠SC中表达的miRNA中，miR-34a和miR-140分别被确定为SC去分化/增殖和髓鞘再生的功能调节剂。我们发现，miR-34a与去分化和增殖的阳性调节子如Notch1和Ccnd1相互作用，以控制SC中的细胞周期动力学。 miR-140靶向转录因子Egr2（髓鞘形成的主要调控因子），并在DRG / SC共培养中调节髓鞘形成。总之，这些结果表明，SC miRNA是神经损伤后SC再生反应的重要调节剂。

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