Myelin Growth Research Articles

Diosgenin ameliorates cellular and molecular changes in multiple sclerosis in C57BL/6 mice

Multiple sclerosis (MS) is especially known as a demyelinating disease of the central nervous system. Current treatments for MS are mostly based on controlling neuroinflammation and there are no treatments to promote the remyelination process at present. Diosgenin is a known herbal anti-inflammatory and antioxidant agent, which has also been shown to stimulate the growth of myelin in vitro. However, there is no or little evidence about diosgenin effects; specially on myelination, neuroprotection and its corresponding mechanisms in vivo in experimental autoimmune encephalomyelitis (EAE) as the most valid experimental model of MS. In this study, the therapeutic effect of diosgenin on clinical signs of EAE, and the corresponding cellular and molecular mechanisms have been examined with emphasis on myelination and neuroprotection mechanisms. EAE was induced using myelin oligodendrocyte glycoprotein (MOG) antigen in C57BL/6 mice. Diosgenin was gavaged (100 mg/kg) daily with the onset of paralysis signs (half tail paralysis) until the 18th post-immunization day in the treatment group. Blood and spinal cord tissue sampling was performed on post-immunization day 18. Lumbar spinal cord inflammation, demyelination, and axonal degeneration were assessed using Hematoxylin and Eosin (H & E), Luxol Fast Blue (LFB), and Bielschowsky's silver staining methods, respectively. Serum and spinal cord tissue level of tumor necrosis factor alpha (TNFα) and tissue levels of matrix metalloproteinase 9 (MMP-9) and interleukin 17 (IL-17) as inflammatory markers, microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A), and activity dependent neuroprotector homeobox (ADNP) as neuroprotective markers were assayed using enzyme linked immunosorbent assay (ELISA) method. The clinical score of EAE in the diosgenin treatment group was significantly reduced compared to the EAE group on days 15 to 18 after induction of the EAE (p < 0.001). Inflammation, demyelination and axonal loss scores also decreased significantly in the diosgenin treatment group compared to the EAE group (p < 0.05). Serum and spinal cord tissue level of TNFα and tissue level of MMP-9 considerably decreased in the diosgenin treatment group in comparison with the EAE group (p < 0.01). Diosgenin treatment had no significant effects on the tissue levels of IL-17, ADNP and MAP1LC3A. Therefore, diosgenin improved the clinical signs of EAE through lowering neuroinflammation, demyelination and axonal degeneration, but did not significantly affect the neuroprotective factors in this study. As a result, diosgenin could be a good candidate for new MS treatment strategies that, in addition to their anti-inflammatory effects, also enhance myelination.

Mek/ERK1/2-MAPK and PI3K/Akt/mTOR signaling plays both independent and cooperative roles in Schwann cell differentiation, myelination and dysmyelination.

Multiple signals are involved in the regulation of developmental myelination by Schwann cells and in the maintenance of a normal myelin homeostasis throughout adult life, preserving the integrity of the axons in the PNS. Recent studies suggest that Mek/ERK1/2-MAPK and PI3K/Akt/mTOR intracellular signaling pathways play important, often overlapping roles in the regulation of myelination in the PNS. In addition, hyperactivation of these signaling pathways in Schwann cells leads to a late onset of various pathological changes in the sciatic nerves. However, it remains poorly understood whether these pathways function independently or sequentially or converge using a common mechanism to facilitate Schwann cell differentiation and myelin growth during development and in causing pathological changes in the adult animals. To address these questions, we analyzed multiple genetically modified mice using simultaneous loss- and constitutive gain-of-function approaches. We found that during development, the Mek/ERK1/2-MAPK pathway plays a primary role in Schwann cell differentiation, distinct from mTOR. However, during active myelination, ERK1/2 is dependent on mTOR signaling to drive the growth of the myelin sheath and regulate its thickness. Finally, our data suggest that peripheral nerve pathology during adulthood caused by hyperactivation of Mek/ERK1/2-MAPK or PI3K is likely to be independent or dependent on mTOR-signaling in different contexts. Thus, this study highlights the complexities in the roles played by two major intracellular signaling pathways in Schwann cells that affect their differentiation, myelination, and later PNS pathology and predicts that potential therapeutic modulation of these pathways in PNS neuropathies could be a complex process.

Effects of omega 3 polyunsaturated fatty acids, antioxidants, and/or non‐steroidal inflammatory drugs in the brain of neonatal rats exposed to intermittent hypoxia

Preterm infants experience frequent arterial oxygen desaturations during oxygen therapy, or intermittent hypoxia (IH). Neonatal IH increases oxidative distress which contributes to neuroinflammation and brain injury. We tested the hypotheses that exposure to neonatal IH is detrimental to the immature brain and that early supplementation with antioxidants and/or omega 3 polyunsaturated fatty acids (n-3 PUFAs) combined with non-steroidal anti-inflammatory drugs (NSAIDs) is protective. Newborn rats were exposed to brief hypoxia (12% O2 ) during hyperoxia (50% O2 ) from the first day of life (P0) until P14 during which they received daily oral supplementation with antioxidants, namely coenzyme Q10 (CoQ10) or glutathione nanoparticles (nGSH), n-3 PUFAs and/or topical ocular ketorolac. Placebo controls received daily oral olive oil and topical ocular saline. Room air (RA) littermates remained in 21% O2 from birth to P21 with all treatments identical. At P14 animals were allowed to recover in RA until P21 with no further treatment. Whole brains were harvested for histopathology and morphometric analyses, and assessed for biomarkers of oxidative stress and inflammation, as well as myelin injury. Neonatal IH resulted in higher brain/body weight ratios, an effect that was reversed with n-3 PUFAs and n-3 PUFAs+CoQ10 with or without ketorolac. Neonatal IH was also associated with hemorrhage, oxidative stress, and elevations in inflammatory prostanoids. Supplementation with n-3 PUFAs and nGSH with and without ketorolac were most beneficial for myelin growth and integrity when administered in RA. However, the benefit of n-3 PUFAs was significantly curtailed in neonatal IH. Neonatal IH during a critical time of brain development causes inflammation and oxidative injury. Loss of therapeutic benefits of n-3 PUFAs suggest its susceptibility to oxidation in neonatal IH and therefore indicate that co-administration with antioxidants may be necessary to sustain its efficacy.

Ketogenic diet-mediated steroid metabolism reprogramming improves the immune microenvironment and myelin growth in spinal cord injury rats according to gene and co-expression network analyses

The ketogenic diet has been widely used in the treatment of various nervous system and metabolic-related diseases. Our previous research found that a ketogenic diet exerts a protective effect and promotes functional recovery after spinal cord injury. However, the mechanism of action is still unclear. In this study, different dietary feeding methods were used, and myelin expression and gene level changes were detected among different groups. We established 15 RNA-seq cDNA libraries from among 4 different groups. First, KEGG pathway enrichment of upregulated differentially expressed genes and gene set enrichment analysis of the ketogenic diet and normal diet groups indicated that a ketogenic diet significantly improved the steroid anabolic pathway in rats with spinal cord injury. Through cluster analysis, protein-protein interaction analysis and visualization of iPath metabolic pathways, it was determined that Sqle, Sc5d, Cyp51, Dhcr24, Msmo1, Hsd17b7, and Fdft1 expression changed significantly. Second, through weighted gene co-expression network analysis showed that rats fed a ketogenic diet showed a significant reduction in the expression of genes involved in immune-related pathways, including those associated with immunity and infectious diseases. A ketogenic diet may improve the immune microenvironment and myelin growth in rats with spinal cord injury through reprogramming of steroid metabolism.

Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy

Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 (MTMR2) gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3P and PtdIns(3,5)P2, with a preference for PtdIns(3,5)P2 A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3'-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5)P2 levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5)P2 synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.

Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth

Inherited peripheral neuropathies (IPNs) represent a broad group of disorders including Charcot-Marie-Tooth (CMT) neuropathies characterized by defects primarily arising in myelin, axons, or both. The molecular mechanisms by which mutations in nearly 100 identified IPN/CMT genes lead to neuropathies are poorly understood. Here we show that the Ras-related GTPase Rab35 controls myelin growth via complex formation with the myotubularin-related phosphatidylinositol (PI) 3-phosphatases MTMR13 and MTMR2, encoded by genes responsible for CMT-types 4B2 and B1 in humans, and found that it downregulates lipid-mediated mTORC1 activation, a pathway known to crucially regulate myelin biogenesis. Targeted disruption of Rab35 leads to hyperactivation of mTORC1 signaling caused by elevated levels of PI 3-phosphates and to focal hypermyelination in vivo. Pharmacological inhibition of phosphatidylinositol 3,5-bisphosphate synthesis or mTORC1 signaling ameliorates this phenotype. These findings reveal a crucial role for Rab35-regulated lipid turnover by myotubularins to repress mTORC1 activity and to control myelin growth.

Childhood socio‐economic disadvantage predicts reduced myelin growth across adolescence and young adulthood

Socio‐economic disadvantage increases exposure to life stressors. Animal research suggests early life stressors impact later neurodevelopment, including myelin developmental growth. To determine how early life disadvantage may affect myelin growth in adolescence and young adulthood, we analysed data from an accelerated longitudinal neuroimaging study measuring magnetisation transfer (MT), a myelin‐sensitive marker, in 288 participants (149 female) between 14 and 25 years of age at baseline. We found that early life economic disadvantage before age 12, measured by a neighbourhood poverty index, was associated with slower myelin growth. This association was observed for magnetization transfer in cortical, subcortical and core white matter regions, and also in key subcortical nuclei. Participant IQ at baseline, alcohol use, body mass index, parental occupation and self‐reported parenting quality did not account for these effects, but parental education did so partially. Specifically, positive parenting moderated the effect of socio‐economic disadvantage in a protective manner. Thus, early socioeconomic disadvantage appears to alter myelin growth across adolescence. This finding has potential translational implications, including clarifying whether reducing socio‐economic disadvantage during childhood, and increasing parental education and positive parenting, promote normal trajectories of brain development in economically disadvantaged contexts.

Anchors Away: Glia-Neuron Adhesion Regulates Myelin Targeting and Growth.

Myelination in the CNS requires oligodendrocytes to first select correct axonal targets and then extend their membranes around and along these axons. In this issue of Developmental Cell, Klingseisen etal. (2019) find that the adhesion protein Neurofascin is required in oligodendrocytes for both target selection and myelin growth.

Benzoic acid derivative-modified chitosan-g-poly(N-isopropylacrylamide): Methoxylation effects and pharmacological treatments of Glaucoma-related neurodegeneration

Long-acting drug delivery systems with advanced functionalities are critically important to pharmacologically treat glaucomatous optic neuropathy, a chronic and multifactorial neurodegenerative disease. Here, a novel strategy based on the methoxylation effects of benzoic acid derivatives was exploited to rationally design a biodegradable and injectable thermogel, which possesses potent antioxidant activities and sustained drug delivery abilities for treating glaucomatous nerve damage. In particular, 4-hydroxy-3,5-dimethoxybenzoic acid, consisting of two methoxyl groups and one hydroxyl group at the position para to the carboxylic group, was demonstrated to contribute to the strong antioxidant activities of a chitosan-g-poly(N-isopropylacrylamide) biomaterial while maintaining the drug encapsulation/release efficiencies of the thermogel. The pharmacological treatment relies on the intracameral injection of the thermogel coloaded with pilocarpine and RGFP966 and exhibits significant improvement in the attenuation of neurodegeneration via suppressing oxidative stress, lowering ocular hypertension, reducing retinal ganglion cell loss and enhancing myelin growth and neuron regeneration. These findings on the development of long-acting drug delivery systems with extended functions show great promise for the management of glaucoma-related neurodegeneration.

White matter tract myelin maturation and its association with general psychopathology in adolescence and early adulthood.

Adolescence is a time period associated with marked brain maturation that coincides with an enhanced risk for onset of psychiatric disorder. White matter tract myelination, a process that continues to unfold throughout adolescence, is reported to be abnormal in several psychiatric disorders. Here, we ask whether psychiatric vulnerability is linked to aberrant developmental myelination trajectories. We assessed a marker of myelin maturation, using magnetisation transfer (MT) imaging, in 10 major white matter tracts. We then investigated its relationship to the expression of a general psychopathology “p‐factor” in a longitudinal analysis of 293 healthy participants between the ages of 14 and 24. We observed significant longitudinal MT increase across the full age spectrum in anterior thalamic radiation, hippocampal cingulum, dorsal cingulum and superior longitudinal fasciculus. MT increase in the inferior fronto‐occipital fasciculus, inferior longitudinal fasciculus and uncinate fasciculus was pronounced in younger participants but levelled off during the transition into young adulthood. Crucially, longitudinal MT increase in dorsal cingulum and uncinate fasciculus decelerated as a function of mean p‐factor scores over the study period. This suggests that an increased expression of psychopathology is closely linked to lower rates of myelin maturation in selective brain tracts over time. Impaired myelin growth in limbic association fibres may serve as a neural marker for emerging mental illness during the course of adolescence and early adulthood.

Two adhesive systems cooperatively regulate axon ensheathment and myelin growth in the CNS

Central nervous system myelin is a multilayered membrane produced by oligodendrocytes to increase neural processing speed and efficiency, but the molecular mechanisms underlying axonal selection and myelin wrapping are unknown. Here, using combined morphological and molecular analyses in mice and zebrafish, we show that adhesion molecules of the paranodal and the internodal segment work synergistically using overlapping functions to regulate axonal interaction and myelin wrapping. In the absence of these adhesive systems, axonal recognition by myelin is impaired with myelin growing on top of previously myelinated fibers, around neuronal cell bodies and above nodes of Ranvier. In addition, myelin wrapping is disturbed with the leading edge moving away from the axon and in between previously formed layers. These data show how two adhesive systems function together to guide axonal ensheathment and myelin wrapping, and provide a mechanistic understanding of how the spatial organization of myelin is achieved.

Effects of the transcription factor Olig1 on the differentiation and remyelination of oligodendrocyte precursor cells after focal cerebral ischemia in rats.

The differentiation and maturation of oligodendrocyte precursor cells (OPCs) is important for remyelination in the central nervous system. Nevertheless, this process is often limited and incomplete in ischemic injury. Oligodendrocyte transcription factor 1 (Olig1) is important for the maturation of OPCs and the repair of demyelinated lesions. However, how Olig1 modulates the development of OPCs or the remyelination associated with ischemic injury remains unclear. The present study aimed to examine alterations in OPCs, and the expression of myelin and Olig1, at different time-points after focal cerebral ischemia using immunohistochemistry and western blot techniques to elucidate the role of Olig1 in the maturation of OPCs and remyelination. The present results showed that the expression of Olig1 significantly decreased at 1 day after middle cerebral artery occlusion (MCAO) and returned to normal levels from day 3 to 28. Additionally, Olig1 was found to translocate into the nucleus following ischemia in the brain. The number of OPCs in the ischemic striatum significantly declined at days 1 and 3 following MCAO, and increased at days 7, 14 and 28 compared with the control. The expression of myelin basic protein, a marker of mature oligodendrocytes and myelin, gradually decreased from day 1 to 7 after ischemia and recovered at day 14 and 28; however, the levels were lower than those in the control group. The present results indicated that the restored normal level of Olig1 following ischemia may play an important role in the maturation of OPCs through its translocation into the nucleus, where it may promote the growth and development of myelin under pathological conditions. However, this endogenous recovery mechanism fails to fully repair the demyelinated lesion. The data of the present study may help clinicians understand the expression pattern of Olig1 and its potential role in endogenous remyelination after ischemia, which may have implications for the treatment of diseases that lead to demyelination.

CNS myelination and remyelination depend on fatty acid synthesis by oligodendrocytes.

Oligodendrocytes (OLs) support neurons and signal transmission in the central nervous system (CNS) by enwrapping axons with myelin, a lipid-rich membrane structure. We addressed the significance of fatty acid (FA) synthesis in OLs by depleting FA synthase (FASN) from OL progenitor cells (OPCs) in transgenic mice. While we detected no effects in proliferation and differentiation along the postnatal OL lineage, we found that FASN is essential for accurate myelination, including myelin growth. Increasing dietary lipid intake could partially compensate for the FASN deficiency. Furthermore, FASN contributes to correct myelin lipid composition and stability of myelinated axons. Moreover, we depleted FASN specifically in adult OPCs to examine its relevance for remyelination. Applying lysolecithin-induced focal demyelinating spinal cord lesions, we found that FA synthesis is essential to sustain adult OPC-derived OLs and efficient remyelination. We conclude that FA synthesis in OLs plays key roles in CNS myelination and remyelination.

Independent and cooperative roles of the Mek/ERK1/2-MAPK and PI3K/Akt/mTOR pathways during developmental myelination and in adulthood.

Multiple extracellular and intracellular signals regulate the functions of oligodendrocytes as they progress through the complex process of developmental myelination and then maintain a functionally intact myelin sheath throughout adult life, preserving the integrity of the axons. Recent studies suggest that Mek/ERK1/2-MAPK and PI3K/Akt/mTOR intracellular signaling pathways play important, often overlapping roles in the regulation of myelination. However, it remains poorly understood whether they function independently, sequentially, or converge using a common mechanism to facilitate oligodendrocyte differentiation, myelin growth, and maintenance. To address these questions, we analyzed multiple genetically modified mice and asked whether the deficits due to the conditional loss-of-function of ERK1/2 or mTOR could be abrogated by simultaneous constitutive activation of PI3K/Akt or Mek, respectively. From these studies, we concluded that while PI3K/Akt, not Mek/ERK1/2, plays a key role in promoting oligodendrocyte differentiation and timely initiation of myelination through mTORC1 signaling, Mek/ERK1/2-MAPK functions largely independently of mTORC1 to preserve the integrity of the myelinated axons during adulthood. However, to promote the efficient growth of the myelin sheath, these two pathways cooperate with each other converging at the level of mTORC1, both in the context of normal developmental myelination or following forced reactivation of the myelination program during adulthood. Thus, Mek/ERK1/2-MAPK and the PI3K/Akt/mTOR signaling pathways work both independently and cooperatively to maintain a finely tuned, temporally regulated balance as oligodendrocytes progress through different phases of developmental myelination into adulthood. Therapeutic strategies aimed at targeting remyelination in demyelinating diseases are expected to benefit from these findings.

Regional growth trajectories of cortical myelination in adolescents and young adults: longitudinal validation and functional correlates.

Adolescence is a time of continued cognitive and emotional evolution occurring with continuing brain development involving synaptic pruning and cortical myelination. The hypothesis of this study is that heavy myelination occurs in cortical regions with relatively direct, predetermined circuitry supporting unimodal sensory or motor functions and shows a steep developmental slope during adolescence (12-21years) until young adulthood (22-35years) when further myelination decelerates. By contrast, light myelination occurs in regions with highly plastic circuitry supporting complex functions and follows a delayed developmental trajectory. In support of this hypothesis, cortical myelin content was estimated and harmonized across publicly available datasets provided by the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) and the Human Connectome Project (HCP). The cross-sectional analysis of 226 no-to-low alcohol drinking NCANDA adolescents revealed relatively steeper age-dependent trajectories of myelin growth in unimodal primary motor cortex and flatter age-dependent trajectories in multimodal mid/posterior cingulate cortices. This pattern of continued myelination showed smaller gains when the same analyses were performed on 686 young adults of the HCP cohort free of neuropsychiatric diagnoses. Critically, a predicted correlation between a motor task and myelin content in motor or cingulate cortices was found in the NCANDA adolescents, supporting the functional relevance of this imaging neurometric. Furthermore, the regional trajectory slopes were confirmed by performing longitudinally consistent analysis of cortical myelin. In conclusion, coordination of myelin content and circuit complexity continues to develop throughout adolescence, contributes to performance maturation, and may represent active cortical development climaxing in young adulthood.

A histone deacetylase 3-dependent pathway delimits peripheral myelin growth and functional regeneration.

Deficits in Schwann cell-mediated remyelination impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms mediating block of remyelination remain elusive. Here, through small-molecule screening focusing on epigenetic modulators, we identified histone deacetylase 3 (HDAC3; a histone-modifying enzyme) as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 enhanced myelin growth and regeneration and improved functional recovery after peripheral nerve injury in mice. HDAC3 antagonizes the myelinogenic neuregulin-PI3K-AKT signaling axis. Moreover, genome-wide profiling analyses revealed that HDAC3 represses promyelinating programs through epigenetic silencing while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include the HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann cell-specific deletion of either Hdac3 or Tead4 in mice resulted in an elevation of myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.

De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination.

Myelination calls for a remarkable surge in cell metabolism to facilitate lipid and membrane production. Endogenous fatty acid (FA) synthesis represents a potentially critical process in myelinating glia. Using genetically modified mice, we show that Schwann cell (SC) intrinsic activity of the enzyme essential for de novo FA synthesis, fatty acid synthase (FASN), is crucial for precise lipid composition of peripheral nerves and fundamental for the correct onset of myelination and proper myelin growth. Upon FASN depletion in SCs, epineurial adipocytes undergo lipolysis, suggestive of a compensatory role. Mechanistically, we found that a lack of FASN in SCs leads to an impairment of the peroxisome proliferator-activated receptor (PPAR) γ-regulated transcriptional program. In agreement, defects in myelination of FASN-deficient SCs could be ameliorated by treatment with the PPARγ agonist rosiglitazone ex vivo and in vivo. Our results reveal that FASN-driven de novo FA synthesis in SCs is mandatory for myelination and identify lipogenic activation of the PPARγ transcriptional network as a putative downstream functional mediator.

Evidence for Myelin Sheath Remodeling in the CNS Revealed by In Vivo Imaging

The length of myelin sheaths affects conduction speed along axons and information propagation. It has recently become clear that myelin may be adaptively modified to modulate circuit function, implying that length remodeling of myelin sheaths should occur. However, direct evidence for such events is lacking. We have investigated how myelination patterns are formed, maintained, and remodeled using long-term imaging and myelin ablation in zebrafish. We demonstrate that length differences between myelin sheaths are established by rapid and variable growth within 3days after their formation, independently of their time of formation, and even along discontinuously myelinated axons. Afterward, sheaths continue extending at similar rates tocompensate for overall animal growth. In consequence, once axon myelination patterns are established, they are maintained over long periods of time. We tested whether mature myelin sheaths can remodel by removing individual sheaths from single axons by targeted ablation. Remarkably, extensive changes in sheath length and number occurred, which frequently restored the original myelination pattern. Our results show that axons can control myelin growth and remodeling, and we provide evidence for a homeostatic control of axon myelination patterns by maintenance and remodeling of myelin sheath length, with implications for circuit development, function, and repair.

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.

Myelination and mTOR.

Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1—a signaling hub coordinating cell metabolism—has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K‐Akt, Mek‐Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.