Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

Abstract

Dedifferentiation of myelinating Schwann cells is a key feature of nerve injury and demyelinating neuropathies. We review recent evidence that this dedifferentiation depends on activation of specific intracellular signaling molecules that drive the dedifferentiation program. In particular, we discuss the idea that Schwann cells contain negative transcriptional regulators of myelination that functionally complement positive regulators such as Krox-20, and that myelination is therefore determined by a balance between two opposing transcriptional programs. Negative transcriptional regulators should be expressed prior to myelination, downregulated as myelination starts but reactivated as Schwann cells dedifferentiate following injury. The clearest evidence for a factor that works in this way relates to c-Jun, while other factors may include Notch, Sox-2, Pax-3, Id2, Krox-24, and Egr-3. The role of cell-cell signals such as neuregulin-1 and cytoplasmic signaling pathways such as the extracellular-related kinase (ERK)1/2 pathway in promoting dedifferentiation of myelinating cells is also discussed. We also review evidence that neurotrophin 3 (NT3), purinergic signaling, and nitric oxide synthase are involved in suppressing myelination. The realization that myelination is subject to negative as well as positive controls contributes significantly to the understanding of Schwann cell plasticity. Negative regulators are likely to have a major role during injury, because they promote the transformation of damaged nerves to an environment that fosters neuronal survival and axonal regrowth. In neuropathies, however, activation of these pathways is likely to be harmful because they may be key contributors to demyelination, a situation which would open new routes for clinical intervention. V V C 2008 Wiley-Liss, Inc.

Inflammaging impairs peripheral nerve maintenance and regeneration

“…In longitudinal nerve tissue sections, the increased phospho‐Erk1/2 and cJun signal was partially colocalized and clustered with p75 , a marker for immature and “repair” Schwann cells (Jessen & Mirsky, 2008) (Supporting information Figure S4). Thus, the inflammatory microenvironment in aged peripheral nerves appears to correlate with persistent low‐level, yet insufficient, repair processes.…”

P2X7-mediated Increased Intracellular Calcium Causes Functional Derangement in Schwann Cells from Rats with CMT1A Neuropathy

“…Characterization of SC Cultures-The phenotypic characterization of 5-day-old SC cultures from CMT1A and wild type rats revealed expression of PMP22, MPZ, and MBP, which are up-regulated during terminal SC differentiation and myelination (18), together with L1 and GFAP, which should only be expressed by nonmyelinating SC and immature SC precursors (18,19) (Fig. 1).…”

“…It is well established that expression of myelin proteins is down-regulated in SC cultured in the absence of neurons (18). Indeed, expression of PMP22, MBP, and MPZ was significantly lower in both wild type and CMT1A SC from 25-day-old cultures, compared with the respective SC from 5-day-old cultures.…”

The Role of Timing in Nerve Reconstruction

“…During later phases of the nerve regeneration process, the myelination by ensheathment of the outgrowing axons is promoted by positive regulators between these axons and the different types of Schwann cells, which includes a radial sorting process involving neuregulin-1 (Jessen & Mirsky, 2008). In addition to the role of ERK1/2, recent data also indicate that the transcription factor Pax-3 has a role in differentiation and proliferation of Schwann cells after a peripheral nerve injury (Doddrell et al, 2012).…”