Schwann cell dedifferentiation is independent of mitogenic signaling and uncoupled to proliferation: Role of cAMP and JNK in the maintenance of the differentiated state

Myelinating Schwann cells (SCs) are highly plastic cells that are able to dedifferentiate and re-enter the cell cycle. However, the molecular signals controlling dedifferentiation are not completely understood. Because a connection between mitogenic signaling and myelin loss has been suggested, we investigated the role of cAMP, a strong inducer of the myelinating phenotype, and mitogenic factors activating receptor tyrosine kinases (RTKs) on SC dedifferentiation. We herein provide evidence indicating that cAMP was required to not only initiate but also maintain a state of differentiation because SCs rapidly dedifferentiated and became competent to resume proliferation upon the removal of cAMP stimulation. Surprisingly, isolated SCs could undergo multiple cycles of differentiation and dedifferentiation upon cAMP addition and removal, respectively, in the absence of mitogenic factors and without entering the cell cycle. Conversely, the activation of RTKs and the ERK cascade by a variety of growth factors, including neuregulin, was not sufficient to initiate dedifferentiation in the presence of cAMP. Importantly, a reduction of cAMP triggered dedifferentiation through a mechanism that required JNK, rather than ERK, activity and an induction of the expression of c-Jun, a transcriptional inhibitor of myelination. In summary, the reversible transition from an undifferentiated to a myelinating state was dependent on cAMP but independent of RTK signaling and cell cycle progression, further indicating that dedifferentiation and proliferation are uncoupled and differentially regulated events in SCs.