mTORC1 Is Transiently Reactivated in Injured Nerves to Promote c-Jun Elevation and Schwann Cell Dedifferentiation

Abstract

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.

Disrupting insulin signaling in Schwann cells impairs myelination and induces a sensory neuropathy

“…Many pivotal studies over the past 10 years have eloquently and thoroughly demonstrated the role of the PI3K/AKT/mTOR pathway on SC myelination in vivo (Beirowski et al, 2017;Cotter et al, 2010;Figlia et al, 2017;Goebbels et al, 2012;Norrmén et al, 2014Norrmén et al, , 2018Sherman et al, 2012 Gregorio et al, 2018;Liu et al, 2017;O'Brien et al, 2014;Sullivan et al, 2007). Consistent with diabetic models, we did not observe reduced CMAP amplitude or motor strength/coordination in INSR/IGF1R SCKO mice.…”

“…The PI3K/AKT/mTOR activity is observed early after PNS injury and has been shown to be important for SC dedifferentiation (Norrmén et al, ), so we asked whether INSR/IGFR1 signaling might contribute to these effects. To assess dedifferentiation and debris clearance, we transected the sciatic nerves of WT and SCKO mice and sacrificed the animals 5 days afterward.…”

“…Our study demonstrates that SCs require insulin/IGF1 signaling for proper myelination through a PI3K/AKT/mTOR‐dependent pathway. Many pivotal studies over the past 10 years have eloquently and thoroughly demonstrated the role of the PI3K/AKT/mTOR pathway on SC myelination in vivo (Beirowski et al, ; Cotter et al, ; Figlia et al, ; Goebbels et al, ; Norrmén et al, , ; Sherman et al, ). However, the signals upstream of this pathway have not been as thoroughly investigated.…”

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

“…Our previous analysis of uninjured nerves had revealed an increase in p-AKT in the cKO (Ma et al 2015), and at 1 d after injury, there was a similar increase in AKT phosphorylation at Thr308 and Ser473, which are catalyzed by PDK1 and mTORC2, respectively (Andjelković et al 1997; Sarbassov et al 2005) (Figure 2). At 1 d after injury, there is little change in p-AKT in wild type mice (Norrmén et al 2018; Ronchi et al 2016). …”

Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves

“…Nevertheless, a number of intracellular pathways that potentially regulate c‐Jun levels have been identified. This includes the Rac1–MKK7–JNK pathway and mTORC, which elevate c‐Jun and have been implicated as upstream activators of c‐Jun after nerve injury, and the cAMP pathway that suppresses c‐Jun (Arthur‐Farraj et al, ; Monje, Soto, Bacallao, & Wood, ; Norrmén et al, ; Shin et al, ). Histone deacetylase 2 (HDAC2), which is activated in injured nerves, also downregulates c‐Jun (Brügger et al, ; reviewed in Jacob, ).…”