Schwann Cell Plasticity Research Articles

Transcriptional inhibition in Schwann cell development and nerve regeneration

Schwann cells, the myelinating glial cells of the peripheral nervous system are remarkably plastic after nerve trauma. Their transdifferentiation into specialized repair cells after injury shares some features with their development from the neural crest. Both processes are governed by a tightly regulated balance between activators and inhibitors to ensure timely lineage progression and allow re-maturation after nerve injury. Functional recovery after injury is very successful in rodents, however, in humans, lack of regeneration after nerve trauma and loss of function as the result of peripheral neuropathies represents a significant problem. Our understanding of the basic molecular machinery underlying Schwann cell maturation and plasticity has made significant progress in recent years and novel players have been discovered. While the transcriptional activators of Schwann cell development and nerve repair have been well defined, the mechanisms counteracting negative regulation of (re-)myelination are less well understood. Recently, transcriptional inhibition has emerged as a new regulatory mechanism in Schwann cell development and nerve repair. This mini-review summarizes some of the regulatory mechanisms controlling both processes and the novel concept of “inhibiting the inhibitors” in the context of Schwann cell plasticity.

Loss of Schwann cell plasticity in chronic inflammatory demyelinating polyneuropathy (CIDP).

BackgroundChronic inflammatory demyelinating polyneuropathy (CIDP) is often associated with chronic disability, which can be accounted to incomplete regeneration of injured axons. We hypothesized that Schwann cell support for regenerating axons may be altered in CIDP, which may account for the poor clinical recovery seen in many patients.MethodsWe exposed human and rodent Schwann cells to sera from CIDP patients and controls. In a model of chronic nerve denervation, we transplanted these conditioned Schwann cells intraneurally and assessed their capacity to support axonal regeneration by electrophysiology and morphometry.ResultsCIDP-conditioned Schwann cells were less growth supportive for regenerating axons as compared to Schwann cells exposed to control sera. The loss of Schwann cell support was associated with lower levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) in CIDP sera and correlated with altered expression of c-Jun and p57kip2 in Schwann cells. The inactivation of these regulatory factors resulted in an altered expression of neurotrophins including BDNF, GDNF, and NGF in CIDP-conditioned Schwann cells in vitro.ConclusionsOur study provides evidence that pro-regenerative functions of Schwann cells are affected in CIDP. It thereby offers a possible explanation for the clinical observation that in many CIDP patients recovery is incomplete despite sufficient immunosuppressive treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0711-7) contains supplementary material, which is available to authorized users.

Epigenomic reprogramming in peripheral nerve injury.

Epigenomic reprogramming in peripheral nerve injury.

Autophagic myelin destruction by Schwann cells during Wallerian degeneration and segmental demyelination.

As lysosomal hydrolysis has long been suggested to be responsible for myelin clearance after peripheral nerve injury, in this study, we investigated the possible role of autophagolysosome formation in myelin phagocytosis by Schwann cells and its final contribution to nerve regeneration. We found that the canonical formation of autophagolysosomes was induced in demyelinating Schwann cells after injury, and the inhibition of autophagy via Schwann cell-specific knockout of the atg7 gene or pharmacological intervention of lysosomal function caused a significant delay in myelin clearance. However, Schwann cell dedifferentiation, as demonstrated by extracellular signal-regulated kinase activation and c-Jun induction, and redifferentiation were not significantly affected, and thus the entire repair program progressed normally in atg7 knockout mice. Finally, autophagic Schwann cells were also found during segmental demyelination in a mouse model of inflammatory peripheral neuropathy. Together, our findings suggest that autophagy is the self-myelin destruction mechanism of Schwann cells, but mechanistically, it is a process distinct from Schwann cell plasticity for nerve repair.

Contribution of Schwann Cells to Remyelination in a Naturally Occurring Canine Model of CNS Neuroinflammation.

Gliogenesis under pathophysiological conditions is of particular clinical relevance since it may provide evidence for regeneration promoting cells recruitable for therapeutic purposes. There is evidence that neurotrophin receptor p75 (p75NTR)-expressing cells emerge in the lesioned CNS. However, the phenotype and identity of these cells, and signals triggering their in situ generation under normal conditions and certain pathological situations has remained enigmatic. In the present study, we used a spontaneous, idiopathic and inflammatory CNS condition in dogs with prominent lympho-histiocytic infiltration as a model to study the phenotype of Schwann cells and their relation to Schwann cell remyelination within the CNS. Furthermore, the phenotype of p75NTR-expressing cells within the injured CNS was compared to their counter-part in control sciatic nerve and after peripheral nerve injury. In addition, organotypic slice cultures were used to further elucidate the origin of p75NTR-positive cells. In cerebral and cerebellar white and grey matter lesions as well as in the brain stem, p75NTR-positive cells co-expressed the transcription factor Sox2, but not GAP-43, GFAP, Egr2/Krox20, periaxin and PDGFR-α. Interestingly, and contrary to the findings in control sciatic nerves, p75NTR-expressing cells only co-localized with Sox2 in degenerative neuropathy, thus suggesting that such cells might represent dedifferentiated Schwann cells both in the injured CNS and PNS. Moreover, effective Schwann cell remyelination represented by periaxin- and P0-positive mature myelinating Schwann cells, was strikingly associated with the presence of p75NTR/Sox2-expressing Schwann cells. Intriguingly, the emergence of dedifferentiated Schwann cells was not affected by astrocytes, and a macrophage-dominated inflammatory response provided an adequate environment for Schwann cells plasticity within the injured CNS. Furthermore, axonal damage was reduced in brain stem areas with p75NTR/Sox2-positive cells. This study provides novel insights into the involvement of Schwann cells in CNS remyelination under natural occurring CNS inflammation. Targeting p75NTR/Sox2-expressing Schwann cells to enhance their differentiation into competent remyelinating cells appears to be a promising therapeutic approach for inflammatory/demyelinating CNS diseases.

Dynamic Regulation of Schwann Cell Enhancers after Peripheral Nerve Injury

Myelination of the peripheral nervous system is required for axonal function and long term stability. After peripheral nerve injury, Schwann cells transition from axon myelination to a demyelinated state that supports neuronal survival and ultimately remyelination of axons. Reprogramming of gene expression patterns during development and injury responses is shaped by the actions of distal regulatory elements that integrate the actions of multiple transcription factors. We used ChIP-seq to measure changes in histone H3K27 acetylation, a mark of active enhancers, to identify enhancers in myelinating rat peripheral nerve and their dynamics after demyelinating nerve injury. Analysis of injury-induced enhancers identified enriched motifs for c-Jun, a transcription factor required for Schwann cells to support nerve regeneration. We identify a c-Jun-bound enhancer in the gene for Runx2, a transcription factor induced after nerve injury, and we show that Runx2 is required for activation of other induced genes. In contrast, enhancers that lose H3K27ac after nerve injury are enriched for binding sites of the Sox10 and early growth response 2 (Egr2/Krox20) transcription factors, which are critical determinants of Schwann cell differentiation. Egr2 expression is lost after nerve injury, and many Egr2-binding sites lose H3K27ac after nerve injury. However, the majority of Egr2-bound enhancers retain H3K27ac, indicating that other transcription factors maintain active enhancer status after nerve injury. The global epigenomic changes in H3K27ac deposition pinpoint dynamic changes in enhancers that mediate the effects of transcription factors that control Schwann cell myelination and peripheral nervous system responses to nerve injury.

Diminished Schwann Cell Repair Responses Underlie Age-Associated Impaired Axonal Regeneration

The regenerative capacity of the peripheral nervous system declines with age. Why this occurs, however, is unknown. We demonstrate that 24-month-old mice exhibit an impairment of functional recovery after nerve injury compared to 2-month-old animals. We find no difference in the intrinsic growth capacity between aged and young sensory neurons in vitro or in their ability to activate growth-associated transcriptional programs after injury. Instead, using age-mismatched nerve transplants in vivo, we show that the extent of functional recovery depends on the age of the nerve graft, and not the age of the host. Molecular interrogation of the sciatic nerve reveals that aged Schwann cells (SCs) fail to rapidly activate a transcriptional repair program after injury. Functionally, aged SCs exhibit impaired dedifferentiation, myelin clearance, and macrophage recruitment. These results suggest that the age-associated decline in axonal regeneration results from diminished Schwann cell plasticity, leading to slower myelin clearance.

Mitogen Activated Protein Kinase Family Proteins and c-jun Signaling in Injury-induced Schwann Cell Plasticity.

Schwann cells (SCs) in the peripheral nerves myelinate axons during postnatal development to allow saltatory conduction of nerve impulses. Well-organized structures of myelin sheathes are maintained throughout life unless nerves are insulted. After peripheral nerve injury, unidentified signals from injured nerves drive SC dedifferentiation into an immature state. Dedifferentiated SCs participate in axonal regeneration by producing neurotrophic factors and removing degenerating nerve debris. In this review, we focus on the role of mitogen activated protein kinase family proteins (MAP kinases) in SC dedifferentiation. In addition, we will highlight neuregulin 1 and the transcription factor c-jun as upstream and downstream signals for MAP kinases in SC responses to nerve injury.

Expression of c‐Jun and Sox‐2 in human schwannomas and traumatic neuromas

Schwann cells myelinate axons of the peripheral nervous system. This process of myelination is regulated by various transcription factors. c-Jun and Sox-2 are negative regulators of myelination and control Schwann cell differentiation and plasticity. Schwannoma cells within tumours no longer express myelin markers, and show increased proliferation and decreased apoptosis. We have shown previously that several signalling pathways are activated in schwannoma cells in situ, in particular the c-Jun N-terminal kinase (JNK) pathway. Both in vitro and in vivo we have demonstrated that c-Jun and Sox-2 are co-regulated in Schwann cells and evidence shows that both these proteins regulate myelination negatively. In this study, we aimed to characterize the expression of c-Jun and Sox-2 in schwannoma and traumatic neuroma. Immunohistochemistry using antibodies to c-Jun and Sox-2 was applied to six schwannomas, and the results were compared with those seen in traumatic neuroma and normal nerve. Increased expression of c-Jun and Sox-2 was seen in schwannoma. We have demonstrated increased expression of c-Jun and Sox-2 in schwannoma compared to traumatic neuroma. There was no expression of c-Jun and Sox-2 in a histologically normal peripheral nerve.

GABA-B receptors in the PNS have a role in Schwann cells differentiation?

γ-aminobutyric acid type B (GABA-B) receptor mediates the inhibitory transmission of γ-aminobutyric acid in the mammalian nervous system, being present in neurons and also in glial cells. Recently the presence of GABA-B has been demonstrated in Schwann cells (SC) suggesting its contribution in regulating the cell fate, maturation, and plasticity. Here, we further support the functional presence of GABA-B receptor in SC plasma membrane. By confocal microscopy immunofluorescence we provide evidences that GABA-B localization on the cell elongated processes correlates with the morphological changes occurring in the differentiated SC. In vivo most of the GABA-B receptors seem to be present in non-myelinating SC, which are committed to ensheath the nociceptive fibers. Therefore, we argue that GABA-B receptors do not control exclusively the in vivo differentiation yielding the myelinating SC, but are also fundamental in regulating the SC plasticity versus the non-myelinating state. Data from the literature and our recent findings corroborate the role of the GABAergic system and GABA-B receptors in the peripheral nervous system, opening new perspectives on the mechanisms controlling the differentiation of SC.

Proliferating Immature Schwann Cells Contribute to Nerve Regeneration After Ischemic Peripheral Nerve Injury

Schwann cells exhibit a high degree of plasticity in adult peripheral nerves after mechanical injury; they have, therefore, been implicated in promoting nerve regeneration. However, Schwann cell behavior after ischemic injury has not yet been elucidated. To determine how Schwann cell plasticity may contribute to recovery from ischemic neuropathy, we used a rat model in which ischemia was induced in the tibial nerve by a 5-hour occlusion of the supplying arteries. Proliferation of immature Schwann cells that emerged in the injured nerve was evaluated by double immunostaining for the p75 neurotrophin receptor and proliferating cell nuclear antigen. The number of proliferating cell nuclear antigen/p75 neurotrophin receptor double-positive cells increased significantly in 1 to 2 weeks after ischemia and subsequently decreased by 4 weeks. During this time, the postmitotic Schwann cells differentiated into mature cells, as demonstrated with bromodeoxyuridine incorporation, which facilitated axon guidance and subsequent axon remyelination. These results suggest the emergence and proliferation of immature Schwann cells that contribute to nerve regeneration after ischemic injury. The manipulation of this population of proliferating immature Schwann cells may be a useful strategy for treating ischemic peripheral neuropathy.

P38 MAPK Activation Promotes Denervated Schwann Cell Phenotype and Functions as a Negative Regulator of Schwann Cell Differentiation and Myelination

Physical damage to the peripheral nerves triggers Schwann cell injury response in the distal nerves in an event termed Wallerian degeneration: the Schwann cells degrade their myelin sheaths and dedifferentiate, reverting to a phenotype that supports axon regeneration and nerve repair. The molecular mechanisms regulating Schwann cell plasticity in the PNS remain to be elucidated. Using both in vivo and in vitro models for peripheral nerve injury, here we show that inhibition of p38 mitogen-activated protein kinase (MAPK) activity in mice blocks Schwann cell demyelination and dedifferentiation following nerve injury, suggesting that the kinase mediates the injury signal that triggers distal Schwann cell injury response. In myelinating cocultures, p38 MAPK also mediates myelin breakdown induced by Schwann cell growth factors, such as neuregulin and FGF-2. Furthermore, ectopic activation of p38 MAPK is sufficient to induce myelin breakdown and drives differentiated Schwann cells to acquire phenotypic features of immature Schwann cells. We also show that p38 MAPK concomitantly functions as a negative regulator of Schwann cell differentiation: enforced p38 MAPK activation blocks cAMP-induced expression of Krox 20 and myelin proteins, but induces expression of c-Jun. As expected of its role as a negative signal for myelination, inhibition of p38 MAPK in cocultures promotes myelin formation by increasing the number as well as the length of individual myelin segments. Altogether, our data identify p38 MAPK as an important regulator of Schwann cell plasticity and differentiation.

Bers-ERK Schwann Cells Coordinate Nerve Regeneration

In this issue of Neuron, Napoli et al. (2012) demonstrate that elevated ERK/MAPK signaling in Schwann cells is a crucial trigger for Schwann cell dedifferentiation in vivo. Moreover, the authors show that dedifferentiated Schwann cells have the potential to coordinate much of the peripheral nerve response to injury.

C-Jun expression in human neuropathies: a pilot study

Schwann cell dedifferentiation following nerve injury is important to permit neural survival and axonal regrowth. Animal studies have shown that the transcription factor c-Jun is upregulated in Schwann cells of injured and pathological nerves where it acts as an important regulator of Schwann cell plasticity, promoting dedifferentiation and demyelination. This pilot immunohistochemical study investigates whether c-Jun is also upregulated in human neuropathies. We examined c-Jun expression in normal and diseased human nerves, as well as in dermal myelinated nerve fibres. Our findings show that although as predicted c-Jun is rarely expressed in normal nerves, it is expressed in Schwann cell nuclei of pathological nerves as predicted by animal studies. Pathological dermal myelinated nerve fibres also show clear nuclear c-Jun expression. Further studies of c-Jun expression will help clarify its role in human neuropathies.

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling.

The formation of myelin by Schwann cells (SCs) occurs via a series of orchestrated molecular events. We previously used global expression profiling to examine peripheral nerve myelination and identified the NAD(+)-dependent deacetylase Sir-two-homolog 2 (Sirt2) as a protein likely to be involved in myelination. Here, we show that Sirt2 expression in SCs is correlated with that of structural myelin components during both developmental myelination and remyelination after nerve injury. Transgenic mice lacking or overexpressing Sirt2 specifically in SCs show delays in myelin formation. In SCs, we found that Sirt2 deacetylates Par-3, a master regulator of cell polarity. The deacetylation of Par-3 by Sirt2 decreases the activity of the polarity complex signaling component aPKC, thereby regulating myelin formation. These results demonstrate that Sirt2 controls an essential polarity pathway in SCs during myelin assembly and provide insights into the association between intracellular metabolism and SC plasticity.

Schwann cell plasticity after spinal cord injury shown by neural crest lineage tracing

After spinal cord injury (SCI), various cell types are recruited to the lesion site, including Schwann cells, which originate in the neural crest and normally myelinate axons in the peripheral nervous system. Here, we investigated the differentiation states, migration patterns, and roles of neural crest derivatives following SCI, using two transgenic mouse lines carrying neural crest-specific reporters, P0-Cre/Floxed-EGFP and Wnt1-Cre/Floxed-EGFP. In these mice, EGFP is expressed only in the neural crest cell lineage. Immunohistochemical analysis revealed that most of the EGFP(+) cells that infiltrated the lesion site after SCI were Schwann cells. Seven days after SCI, the P0-positive, mature Schwann cells residing at the nerve roots had dedifferentiated into P0(-)/p75(+) immature Schwann cells, which proliferated and began migrating into the lesion site. The dedifferentiation of the Schwann cells was corroborated by their expression of phosphorylated c-Jun, which promotes dedifferentiation and inhibits the expression of myelin-associated genes in the peripheral nerves. Thereafter, the number of EGFP(+)/p75(+) immature Schwann cells decreased and that of EGFP(+)/P0(+) mature cells increased gradually, indicating that the cells redifferentiated into mature Schwann cells within the lesion site. This study draws on the advantages offered by transgenic mouse lines bearing a genetic cell-lineage marker and extends previous work by describing the origins and behavior of the neural crest-derived cells that contribute to endogenous repair after SCI. This process, involving Schwann cell plasticity, is a novel repair mechanism for the lesioned mammalian spinal cord.

Plasticité phénotypique des mélanocytes et des cellules de Schwann

Melanocytes, the pigmented cells of the skin, and the glial Schwann cells lining peripheral nerves are developmentally derived from an early and transient ectodermal structure of the vertebrate embryo, the neural crest, which is also at the origin of multiple neural and non-neural cell types. Besides melanocytes and neural cells of the peripheral nervous system, the neural crest cells give rise to mesenchymal cell types in the head, which form most of the craniofacial skeleton, dermis, fat tissue and vascular musculo-connective components. How such a wide diversity of differentiation fates is established during embryogenesis and is later maintained in adult tissues are among key questions in developmental and stem cell biology. The analysis of the developmental potentials of single neural crest cells cultured in vitro led to characterizing multipotent stem/progenitor cells as well as more restricted precursors in the early neural crest of avian and mammalian embryos. Data support a hierarchical model of the diversification of neural crest lineages through progressive restrictions of multipotent stem cell potentials driven by local environmental factors. In particular, melanocytes and glial Schwann cells were shown to arise from a common bipotent progenitor, which depends upon the peptide endothelin-3 for proliferation and self-renewal ability. In vivo, signaling by endothelin-3 and its receptor is also required for the early development of melanocytes and proper pigmentation of the vertebrate body. It is generally assumed that, after lineage specification and terminal differentiation, specialized cell types, like the melanocytes and Schwann cells, do not change their identity. However, this classic notion that somatic cell differentiation is a stable and irreversible process has been challenged by emerging evidence that dedifferentiation can occur in different biological systems through nuclear transfer, cell fusion, epigenetic modifications and ectopic gene expression. This review considers the issue of whether neural crest-derived lineages are endowed with some phenotypic plasticity. Emphasis is put on the ability of pigment cells and Schwann cells to dedifferentiate and reprogram their fate in vitro. To address this question, we have studied the clonal progeny of differentiated Schwann cells and melanocytes after their isolation from the sciatic nerve and the back skin of quail embryos, respectively. When stimulated to proliferate in vitro in the presence of endothelin-3, both cell types were able to dedifferentiate and produce alternative neural crest-derived cell lineages. Individual Schwann cells isolated by FACS, using a glial-specific surface marker, gave rise in culture to pigment cells and myofibroblasts/smooth muscle cells. Treatment of the cultures with endothelin-3 was required for Schwann cell conversion into melanocytes, which involved acquisition of multipotency. Moreover, Schwann cell plasticity could also be induced in vivo: following transplantation into the branchial arch of a young chick host embryo, dedifferentiating Schwann cells were able to integrate the forming head structures of the host and, specifically, to contribute smooth muscle cells to the wall of cranial blood vessels. We also analyzed the in vitro behavior of individual pigment cells obtained by microdissection and enzymatic treatment of quail epidermis at embryonic and hatching stages. In single cell cultures treated with endothelin-3, pigment cells strongly proliferated while rapidly dedifferentiating into unpigmented cells, leading to the formation of large colonies that comprised glial cells and myofibroblasts in addition to melanocytes. By serially subcloning these primary colonies, we could efficiently propagate a bipotent glial-melanocytic precursor that is generated in the progeny of the melanocytic founder. These data therefore suggest that pigment cells have the ability to revert back to the state of self-renewing neural crest-like progenitors. Altogether, these studies have shown that Schwann cells and pigment cells display an unstable status of differentiation, which can be disclosed if these differentiated cells are displaced out of their native tissue. When challenged with new environmental conditions in vitro, differentiated Schwann cells and pigment cells can reacquire stem cell properties of their neural crest ancestors. Notably, such reprogramming was achieved through the effect of a single exogenous factor and without the need of any induced genetic modification. Deciphering the cellular and molecular mechanisms that regulate the plasticity and maintenance of neural crest-derived differentiated cells is likely to be an important step towards the understanding of the neurocristopathies and cancers that target neural crest derivatives in humans.

Evidence for endothelial nitric oxide as a negative regulator of Schwann cell dedifferentiation after peripheral nerve injury

The loss of intimate contact with axons triggers Schwann cells (SCs) to switch from a myelin-producing phenotype to a dedifferentiated, proliferating non-myelin-forming state after nerve injury. SC dedifferentiation is required for effective nerve regeneration. Negative regulators of SC dedifferentiation are promising targets to accelerate function recovery in acquired peripheral neuropathies. We recently reported that nitric oxide (NO) synthesized by endothelial NO synthase (eNOS) slows down functional recovery and axon regeneration after XIIth nerve crushing. This harmful action could be effected by a NO-delaying action on SC dedifferentiation. Adenoviral vectors directing the expression of a dominant negative mutant for eNOS (AVV-TeNOS) or the enhanced green fluorescent protein (AVV-eGFP) were individually injected into the distal stump just after XIIth nerve crushing. Growth-associated protein 43 (GAP-43), strongly over-expressed in dedifferentiated SCs and regenerating axons, was up-regulated in AVV-TeNOS-transduced nerves relative to AVV-eGFP-treated nerves. AVV-TeNOS increased the number of GAP-43-positive cells and bands of Bungner but did not alter the number of Hoechst-positive nuclei relative to AVV-eGFP. These results signal endothelial NO as a negative regulator of the SC dedifferentiation process, but not of SC proliferation rate, after nerve injury. Vascular-derived factors should be taken into account as feasible extrinsic regulators of SC plasticity.

Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity

Notch signaling is central to vertebrate development, and analysis of Notch has provided important insights into pathogenetic mechanisms in the CNS and many other tissues. However, surprisingly little is known about the role of Notch in the development and pathology of Schwann cells and peripheral nerves. Using transgenic mice and cell cultures, we found that Notch has complex and extensive regulatory functions in Schwann cells. Notch promoted the generation of Schwann cells from Schwann cell precursors and regulated the size of the Schwann cell pool by controlling proliferation. Notch inhibited myelination, establishing that myelination is subject to negative transcriptional regulation that opposes forward drives such as Krox20. Notably, in the adult, Notch dysregulation resulted in demyelination; this finding identifies a signaling pathway that induces myelin breakdown in vivo. These findings are relevant for understanding the molecular mechanisms that control Schwann cell plasticity and underlie nerve pathology, including demyelinating neuropathies and tumorigenesis.

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

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.