mTORC1 Is Transiently Reactivated in Injured Nerves to Promote c-Jun Elevation and Schwann Cell Dedifferentiation.
mTORC1 Is Transiently Reactivated in Injured Nerves to Promote c-Jun Elevation and Schwann Cell Dedifferentiation.
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DOI：
10.1523/jneurosci.3619-17.2018
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发表时间：
2018-05-16
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影响因子：
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通讯作者：
Suter U
中科院分区：
文献类型：
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作者：
Norrmén C;Figlia G;Pfistner P;Pereira JA;Bachofner S;Suter U
雪旺细胞（Schwann cells，SC）具有显著的可塑性。当周围神经损伤时，SC去分化并获得新的功能以协调神经修复，称为修复SC。随后，SC再分化以使再生轴突再髓鞘化。鉴于SC去分化/再分化在损伤的神经和脱髓鞘神经病变之间的相似性，阐明神经损伤后SC可塑性所涉及的信号具有潜在的更广泛的意义。c-Jun已成为调节SC去分化和获得修复SC特征的关键转录因子。然而，神经损伤后控制c-Jun活性的上游途径在很大程度上是未知的。我们报告说，mTORC 1通路是短暂的，但强大的去分化干细胞重新激活。通过小鼠SC（包括雄性和雌性动物）中功能至关重要的mTORC 1亚基Raptor的可诱导遗传缺失，我们发现mTORC 1重新激活对于适当的髓鞘清除、SC去分化和因此的髓鞘再生是必要的，而炎症反应没有重大改变。在没有mTORC 1信号传导的情况下，c-Jun未能正确上调。因此，发现c-Jun结合基序在受损突变体中表达降低的基因的启动子中富集。此外，使用培养的SC，我们发现mTORC 1可能通过eIF 4F亚基eIF 4A通过促进其翻译参与c-Jun调节。这些结果提供的证据表明，神经损伤后适当的c-Jun升高也涉及mTORC 1依赖的转录后调节，以确保及时的SC去分化。脊椎动物的一个重要的进化获得是由CNS中的少突胶质细胞和PNS中的许旺细胞（SC）产生的髓鞘中轴突的再生。当髓磷脂受损时，动作电位沿沿着轴突的传导减慢或被阻断，导致衰弱性疾病。与少突胶质细胞不同，SC具有很高的再生潜力，这是由其显著的可塑性所赋予的。因此，了解SC可塑性的潜在机制可能会发现神经再生和脱髓鞘疾病的新治疗靶点。我们的工作表明，mTORC 1通路在SC中的重新激活对于神经损伤后有效的SC去分化至关重要。因此，调节该信号通路可能在周围神经损伤和其他疾病中具有治疗相关性。
Schwann cells (SCs) are endowed with a remarkable plasticity. When peripheral nerves are injured, SCs dedifferentiate and acquire new functions to coordinate nerve repair as so-called repair SCs. Subsequently, SCs redifferentiate to remyelinate regenerated axons. Given the similarities between SC dedifferentiation/redifferentiation in injured nerves and in demyelinating neuropathies, elucidating the signals involved in SC plasticity after nerve injury has potentially wider implications. c-Jun has emerged as a key transcription factor regulating SC dedifferentiation and the acquisition of repair SC features. However, the upstream pathways that control c-Jun activity after nerve injury are largely unknown. We report that the mTORC1 pathway is transiently but robustly reactivated in dedifferentiating SCs. By inducible genetic deletion of the functionally crucial mTORC1-subunit Raptor in mouse SCs (including male and female animals), we found that mTORC1 reactivation is necessary for proper myelin clearance, SC dedifferentiation, and consequently remyelination, without major alterations in the inflammatory response. In the absence of mTORC1 signaling, c-Jun failed to be upregulated correctly. Accordingly, a c-Jun binding motif was found to be enriched in promoters of genes with reduced expression in injured mutants. Furthermore, using cultured SCs, we found that mTORC1 is involved in c-Jun regulation by promoting its translation, possibly via the eIF4F-subunit eIF4A. These results provide evidence that proper c-Jun elevation after nerve injury involves also mTORC1-dependent post-transcriptional regulation to ensure timely dedifferentiation of SCs. SIGNIFICANCE STATEMENT A crucial evolutionary acquisition of vertebrates is the envelopment of axons in myelin sheaths produced by oligodendrocytes in the CNS and Schwann cells (SCs) in the PNS. When myelin is damaged, conduction of action potentials along axons slows down or is blocked, leading to debilitating diseases. Unlike oligodendrocytes, SCs have a high regenerative potential, granted by their remarkable plasticity. Thus, understanding the mechanisms underlying SC plasticity may uncover new therapeutic targets in nerve regeneration and demyelinating diseases. Our work reveals that reactivation of the mTORC1 pathway in SCs is essential for efficient SC dedifferentiation after nerve injury. Accordingly, modulating this signaling pathway might be of therapeutic relevance in peripheral nerve injury and other diseases.