Graded Elevation of c-Jun in Schwann CellsIn Vivo: Gene Dosage Determines Effects on Development, Remyelination, Tumorigenesis, and Hypomyelination

Abstract

Schwann cell c-Jun is implicated in adaptive and maladaptive functions in peripheral nerves. In injured nerves, this transcription factor promotes the repair Schwann cell phenotype and regeneration and promotes Schwann-cell-mediated neurotrophic support in models of peripheral neuropathies. However, c-Jun is associated with tumor formation in some systems, potentially suppresses myelin genes, and has been implicated in demyelinating neuropathies. To clarify these issues and to determine how c-Jun levels determine its function, we have generated c-Jun OE/+ and c-Jun OE/OE mice with graded expression of c-Jun in Schwann cells and examined these lines during development, in adulthood, and after injury using RNA sequencing analysis, quantitative electron microscopic morphometry, Western blotting, and functional tests. Schwann cells are remarkably tolerant of elevated c-Jun because the nerves of c-Jun OE/+ mice, in which c-Jun is elevated ∼6-fold, are normal with the exception of modestly reduced myelin thickness. The stronger elevation of c-Jun in c-Jun OE/OE mice is, however, sufficient to induce significant hypomyelination pathology, implicating c-Jun as a potential player in demyelinating neuropathies. The tumor suppressor P19ARF is strongly activated in the nerves of these mice and, even in aged c-Jun OE/OE mice, there is no evidence of tumors. This is consistent with the fact that tumors do not form in injured nerves, although they contain proliferating Schwann cells with strikingly elevated c-Jun. Furthermore, in crushed nerves of c-Jun OE/+ mice, where c-Jun levels are overexpressed sufficiently to accelerate axonal regeneration, myelination and function are restored after injury.SIGNIFICANCE STATEMENT In injured and diseased nerves, the transcription factor c-Jun in Schwann cells is elevated and variously implicated in controlling beneficial or adverse functions, including trophic Schwann cell support for neurons, promotion of regeneration, tumorigenesis, and suppression of myelination. To analyze the functions of c-Jun, we have used transgenic mice with graded elevation of Schwann cell c-Jun. We show that high c-Jun elevation is a potential pathogenic mechanism because it inhibits myelination. Conversely, we did not find a link between c-Jun elevation and tumorigenesis. Modest c-Jun elevation, which is beneficial for regeneration, is well tolerated during Schwann cell development and in the adult and is compatible with restoration of myelination and nerve function after injury.

Time‐restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury

“…In other words, Tet-On/c-Jun-modified SCs were not likely to suppress myelination in the later repair stage. Thus, our results and previous findings by Fazal et al (59) indicate that time-restricted expression of c-Jun in SCs is relatively safe and beneficial for nerve repair.…”

“…The present study focused on the controlled expression of the c-Jun gene to provide time-restricted neurotrophic support for nerve regeneration, whereas previous studies have also showed that c-Jun is associated with tumor formation in some systems (56), potentially suppresses myelin genes (57), and has been implicated in demyelinating neuropathies (58). It was reported that more than 1000 genes were regulated by c-Jun in SCs after nerve injury, including the up-regulation of GDNF, sonic hedgehog, oligodendrocyte transcription factor 1, inhibitor of DNA binding 2, SRY-box 2, and runt-related transcription factor 2 and the down-regulation of myelin protein zero, myelin basic protein, and peripheral myelin protein 22 (48,59). Thus, up-regulation of c-Jun in SCs for nerve repair might raise the concern about the side effects of tumor formation and hypomyelination.…”

Transcriptional control of myelination and remyelination

“…Its ability to trigger dedifferentiation results at least in part from its ability to repress Egr2 and to directly antagonize myelin gene expression (Parkinson et al, ; Parkinson et al, ). Effects on proliferative properties and on activation of the repair program likely involve additional downstream mediators such as Runx2, the activator of the unfolded protein response Chop or specific microRNAs (Arthur‐Farraj et al, ; Hung, Sun, Keles, & Svaren, ), and are sensitive to the exact cJun levels (Fazal et al, ).…”

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

“…As a result, regeneration of motor and sensory axons, and the survival of sensory neurons and facial motor neurons are severely compromised if Schwann cell c-Jun is inactivated. Conversely, in situations where normal regeneration is impaired, such as after chronic denervation and in aging animals, enhanced expression of Schwann cell c-Jun promotes axonal regeneration(Parkinson et al, 2008;Arthur-Farraj et al, 2012;Fontana et al, 2012;Fazal et al, 2017;Wagstaff et al, 2017;Figlia, Gerber, & Suter, 2018). Interestingly, macrophage recruitment and Schwann cell numbers, at least at early time points after injury, are less affected in the absence of c-Jun than other aspects of the injury response(Arthur-Farraj et al, 2012).…”