期刊
JOURNAL OF NEUROSCIENCE
卷 38, 期 20, 页码 4811-4828出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3619-17.2018
关键词
differentiation; injury; mTOR; myelination; nerve; Schwann cells
资金
- Swiss National Science Foundation
- Marie Curie Intra-European Fellowship within the 7th European Community framework, Instrumentariumin Tiedesaatio and Medicinska Understodsforeningen Liv och Halsa
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 mTORCl pathway is transiently but robustly reactivated in dedifferentiating SCs. By inducible genetic deletion of the functionally crucial mTORCl-subunit Raptor in mouse SCs (including male and female animals), we found that mTORCl reactivation is necessary for proper myelin clearance, SC dedifferentiation, and consequently remyelination, without major alterations in the inflammatory response. In the absence of mTORCl 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 mTORCl 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 mTORCl -dependent posttranscriptional regulation to ensure timely dedifferentiation of SCs.
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