Sustained MAPK/ERK Activation in Adult Schwann Cells Impairs Nerve Repair

The MAPK/ERK pathway has a critical role in PNS development. It is required for Schwann cell (SC) differentiation and myelination; sustained embryonic MAPK/ERK activation in SCs enhances myelin growth overcoming signals that normally end myelination. Excess activation of this pathway can be maladaptive as in adulthood acute strong activation of MAPK/ERK has been shown to cause SC dedifferentiation and demyelination. We used a mouse model (including male and female animals) in which the gain-of-function MEK1DD allele produces sustained MAPK/ERK activation in adult SCs, and we determined the impact of such activation on nerve repair. In the uninjured nerve, MAPK/ERK activation neither impaired myelin nor reactivated myelination. However, in the injured nerve it was detrimental and resulted in delayed repair and functional recovery. In the early phase of injury, the rate of myelin clearance was faster. Four weeks following injury, when nerve repair is normally advanced, myelinated axons of MEK1DD mutants demonstrated higher rates of myelin decompaction, a reduced number of Cajal bands. and decreased internodal length. We noted the presence of abnormal Remak bundles with long SCs processes and reduced numbers of C-fibers/Remak bundle. Both the total number of regenerating axons and the intraepidermal nerve fiber density in the skin were reduced. Sustained activation of MAPK/ERK in adult SCs is therefore deleterious to successful nerve repair, emphasizing the differences in the signaling processes coordinating nerve development and repair. Our results also underline the key role of SCs in axon regeneration and successful target reinnervation.

SIGNIFICANCE STATEMENT The MAPK/ERK pathway promotes developmental myelination and its sustained activation in SCs induced continuous myelin growth, compensating for the absence of essential myelination signals. However, the strength of activation is fundamental because acute strong induction of MAPK/ERK in adulthood induces demyelination. What has been unknown is the effect of a mild but sustained MAPK/ERK activation in SCs on nerve repair in adulthood. This promoted myelin clearance but led to abnormalities in nonmyelinating and myelinating SCs in the later phases of nerve repair, resulting in slowed axon regeneration, cutaneous reinnervation, and functional recovery. Our results emphasize the distinct role of the MAPK/ERK pathway in developmental myelination versus remyelination and the importance of signaling between SCs and axons for successful axon regeneration.