Fazal, SV;
Gomez-Sanchez, JA;
Wagstaff, LJ;
Musner, N;
Otto, G;
Janz, M;
Mirsky, R;
(2017)
Graded elevation of c-Jun in Schwann cells in vivo: gene dosage determines effects on development, re-myelination, tumorigenesis and hypomyelination.
Journal of Neuroscience
, 37
(50)
pp. 12297-12313.
10.1523/JNEUROSCI.0986-17.2017.
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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 it promotes Schwann cell mediated neurotrophic support in models of peripheral neuropathies. However, c-Jun is associated with tumour formation in some systems, it potentially supresses myelin genes, and has been implicated in demyelinating neuropathies. To clarify these issues, and 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, since the nerves of c-Jun OE/+ mice, where c-Jun in elevated about six 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 tumour 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 tumours, in agreement with the fact that tumours 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 over-expressed sufficiently to accelerate axonal regeneration, myelination and function are restored after injury.SIGNIFICANCE STATEMENTIn injured and diseased nerves, the transcription factor c-Jun in Schwann cells is elevated, and variously implicated in controlling beneficial or adverse functions, including the trophic Schwann cell support for neurons, promotion of regeneration, tumorigenesis and suppression of myelination. To analyse 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, since it inhibits myelination. On the other hand, we do 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.
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