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Predicted cytoskeletal signaling pathways at the leading edge of myelinating cells. a The leading edge of an OPC process is the cytoplasmic rich expansion that comes into contact with an axon, which then becomes the inner tongue during myelin wrapping. The inner tongue remains in close contact with the axon as it ensheathes the axon and continues to wrap during active myelination. RhoGTPases Rac1 and Cdc42 signal through WAVE or N-WASP and then the Arp2/3 complex to promote actin polymerization. RhoGTPases can also signal through the PAK proteins to phosphorylate LIMK, that then phosphorylates and inactivates cofilin to regulate actin turnover. Active (unphosphorylated) cofilin binds to F-actin, induces a local twist in the filament, leading to actin severing. High levels of cofilin bound to F-actin can induce twisting throughout the entire filament, changing cofilin activity to an actin stabilizing protein. b Longitudinal view of a myelinated axon with areas of open cytoplasmic channels that close upon myelin compaction. c Cross section of myelinated axon. F-actin localizes to cytoplasmic channels, allowing access from the outer tongue of myelin to the axon-myelin interface and the inner tongue
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Myelinating cells of both the peripheral and central nervous systems (CNSs) undergo dramatic cytoskeletal reorganization in order to differentiate and produce myelin. Myelinating oligodendrocytes in the CNS show a periodic actin pattern, demonstrating tight regulation of actin. Furthermore, recent data demonstrate that actin polymerization drives e...
Citations
... The assembly and extension of actin filaments in newly formed oligodendrocytes are likely to occur with various bundling elements, such as coronins and capsin. The high expression of these actin dynamics-related proteins in myelinating oligodendrocytes also facilitates the disassembly and stabilization of actin filaments (Brown & Macklin, 2020). Actin-binding proteins act as crosslinkers and intermediaries for extracellular signals through cell adhesion molecules (e.g., FAK, integrin, and paxillin) and intracellular signals such as Arf6-mediated membrane trafficking (Torii et al., 2010) and Arf1-mediated paxillin recruitment to the plasma membrane (Norman et al., 1998) in migrating cells. ...
During myelination, large quantities of proteins are synthesized and transported from the endoplasmic reticulum (ER)‐trans‐Golgi network (TGN) to their appropriate locations within the intracellular region and/or plasma membrane. It is widely believed that oligodendrocytes uptake neuronal signals from neurons to regulate the endocytosis‐ and exocytosis‐mediated intracellular trafficking of major myelin proteins such as myelin‐associated glycoprotein (MAG) and proteolipid protein 1 (PLP1). The small GTPases of the adenosine diphosphate (ADP) ribosylation factor (Arf) family constitute a large group of signal transduction molecules that act as regulators for intracellular signaling, vesicle sorting, or membrane trafficking in cells. Studies on mice deficient in Schwann cell–specific Arfs‐related genes have revealed abnormal myelination formation in peripheral nerves, indicating that Arfs‐mediated signaling transduction is required for myelination in Schwann cells. However, the complex roles in these events remain poorly understood. This review aims to provide an update on signal transduction, focusing on Arf and its activator ArfGEF (guanine nucleotide exchange factor for Arf) in oligodendrocytes and Schwann cells. Future studies are expected to provide important information regarding the cellular and physiological processes underlying the myelination of oligodendrocytes and Schwann cells and their function in modulating neural activity. image
... In CNS development, each myelin sheath is derived from a lamellipod connected by a narrow cell process to the oligodendrocyte soma. Growth of the prospective sheath involves actin remodelling (reviewed in Brown and Macklin, 2020) at the lamellipod's leading edge (future 'inner tongue'), which advances in a myelin basic protein-(MBP) -dependent fashion around the axon, underneath accumulating numbers of membrane wraps (Nawaz et al., 2015;Snaidero et al., 2014;Zuchero et al., can be visualised in cytosolic spaces of flattened myelin-like sheets in oligodendrocyte monolayer cultures (Ainger et al., 1993;Carson et al., 1997;Kachar et al., 1986;Song et al., 2003), we additionally hypothesized that myelinic channels might serve as a route for the movement of membranous cargo to the glial-axonal junction, analogous to axonal transport to synaptic terminals. ...
Myelin sheaths comprise compacted layers of oligodendroglial membrane wrapped spirally around axons. Each sheath, if imagined unwrapped, has a cytoplasm-filled space at its perimeter, linking it to the oligodendrocyte soma via a short process. By electron microscopy (EM), this space, which we term the 'myelinic channel system' contains microtubules and membranous organelles, but whether these are remnants of development or serve a function is unknown. Performing live imaging of myelinating oligodendrocytes expressing fluorescent reporters, we found that the myelinic channel system serves microtubule-dependent organelle transport. Further, the intra-myelinic movement of peroxisomes was modulated by neuronal electrical activity in these mixed neural cell cultures. Loss of oligodendroglial Kif21b or CNP in vivo led to apparent stasis of myelin organelles and secondary axon pathology. This suggests that oligodendrocytes require motor transport in the myelinic channel system to maintain axonal integrity.
... Myelin loss was one of the earliest reported observations in the postmortem AD brain 44 . Cytoskeleton reorganization and the regulation of actin are key to the myelination process 45 . Our results emphasized that the negative regulation of these processes is predictive of the AD condition. ...
Late onset Alzheimer’s disease (AD) is a progressive neurodegenerative disease, with brain changes beginning years before symptoms surface. AD is characterized by neuronal loss, the classic feature of the disease that underlies brain atrophy. However, GWAS reports and recent single-nucleus RNA sequencing (snRNA-seq) efforts have highlighted that glial cells, particularly microglia, claim a central role in AD pathophysiology. Here, we tailor pattern-learning algorithms to explore distinct gene programs by integrating the entire transcriptome, yielding distributed AD-predictive modules within the brain’s major cell-types. We show that these learned modules are biologically meaningful through the identification of new and relevant enriched signaling cascades. The predictive nature of our modules, especially in microglia, allows us to infer each subject’s progression along a disease pseudo-trajectory, confirmed by post-mortem pathological brain tissue markers. Additionally, we quantify the interplay between pairs of cell-type modules in the AD brain, and localized known AD risk genes to enriched module gene programs. Our collective findings advocate for a transition from cell-type-specificity to gene modules specificity to unlock the potential of unique gene programs, recasting the roles of recently reported genome-wide AD risk loci.
... In the intact, injured, and diseased CNS, OPCs pass through multiple transitionary stages to differentiate into myelinating OLs: proliferative OPCs, pre-OLs, immature differentiated OLs, and mature myelinating OLs (Tiane et al., 2019). Progression of OL-lineage cells through these stages is driven by stage-specific alterations of signaling pathways (Adams et al., 2021) that coordinate protein and lipid synthesis and promote cytoskeleton reorganization (Figlia et al., 2018;Brown and Macklin, 2019). Cytoskeletal dynamics are important at multiple stages. ...
... Cytoskeletal dynamics are important at multiple stages. For example, actin polymerization drives early OPC differentiation and the extension of OPCs processes toward axons for ensheathment, while actin depolymerization drives myelin compaction (Brown and Macklin, 2019). Thus, actin polymerizing regulators are enriched in differentiating and premyelinating OLs, whereas actin depolymerizing regulators (e.g. ...
... Because cytoskeletal reorganization is influenced by the mTOR pathways (Oh and Jacinto, 2011) and is important in OPC differentiation and myelination (Brown and Macklin, 2019), Dahl et al. (2023) investigated actin polymerization and depolymerization regulators in the Rictor cKO corpus callosum. Specifically, profilin (involved in polymerization of G-actin into F-actin) and gelsolin (involved in Ca 21 -dependent actin filament severing and depolymerization) levels were examined (Thomason et al., 2020). ...
... Oligodendroglial Vangl2, a RhoA-Myosin II-dependent planar polarity protein, controls paranodal axon diameter 79 , demonstrating some compressive action of the paranodal spiral on the axon. Developmental process extension by oligodendrocytes at the leading edge of myelin sheaths involves actin dynamics 59,80 . Oligodendrocytes are also known to increase cytoskeletal plasticity after inflammatory damage, which is associated with early changes at the paranodal domains 58,81 . ...
Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.
... indicating tight cytoskeletal regulation during myelination (Brown & Macklin, 2019). In addition, one study indicates that actin polymerization in the leading edge is the main force driving the wrapping process, while actin depolymerization promotes membrane spreading by reducing surface tension (Nawaz et al., 2015). ...
Myelination contributes not only to the rapid nerve conduction but also to axonal insulation and protection. In the central nervous system (CNS), the initial myelination features a multistep process where oligodendrocyte precursor cells undergo proliferation and migration before differentiating into mature oligodendrocytes. Mature oligodendrocytes then extend processes and wrap around axons to form the multilayered myelin sheath. These steps are tightly regulated by various cellular and molecular mechanisms, such as transcription factors (Olig family, Sox family), growth factors (PDGF, BDNF, FGF-2, IGF), chemokines/cytokines (TGF-β, IL-1β, TNFα, IL-6, IFN-γ), hormones (T3), axonal signals (PSA-NCAM, L1-CAM, LINGO-1, neural activity), and intracellular signaling pathways (Wnt/β-catenin, PI3 K/AKT/mTOR, ERK/MAPK). However, the fundamental mechanisms for initial myelination are yet to be fully elucidated. Identifying pivotal mechanisms for myelination onset, development, and repair will become the focus of future studies. This review focuses on the current understanding of how CNS myelination is initiated and also the regulatory mechanisms underlying the process.
... Activation of the innate immune system and signaling through extracellular membrane receptors was enriched in oligodendrocytes, suggesting cell-cell interactions between oligodendrocytes and immune cells and perhaps signaling from SASP factors in the extracellular environment. Dysregulation of actin dynamics was evident, suggesting alterations in myelination (Brown and Macklin, 2020). ...
Mild traumatic brain injury (mTBI) is an important public health issue, as it can lead to long-term neurological symptoms and risk of neurodegenerative disease. The pathophysiological mechanisms driving this remain unclear, and currently there are no effective therapies for mTBI. In this study on repeated mTBI (rmTBI), we have induced three mild closed-skull injuries or sham procedures, separated by 24 h, in C57BL/6 mice. We show that rmTBI mice have prolonged righting reflexes and astrogliosis, with neurological impairment in the Morris water maze (MWM) and the light dark test. Cortical and hippocampal tissue analysis revealed DNA damage in the form of double-strand breaks, oxidative damage, and R-loops, markers of cellular senescence including p16 and p21, and signaling mediated by the cGAS-STING pathway. This study identified novel sex differences after rmTBI in mice. Although these markers were all increased by rmTBI in both sexes, females had higher levels of DNA damage, lower levels of the senescence protein p16, and lower levels of cGAS-STING signaling proteins compared to their male counterparts. Single-cell RNA sequencing of the male rmTBI mouse brain revealed activation of the DNA damage response, evidence of cellular senescence, and pro-inflammatory markers reminiscent of the senescence-associated secretory phenotype (SASP) in neurons and glial cells. Cell-type specific changes were also present with evidence of brain immune activation, neurotransmission alterations in both excitatory and inhibitory neurons, and vascular dysfunction. Treatment of injured mice with the senolytic drug ABT263 significantly reduced markers of senescence only in males, but was not therapeutic in females. The reduction of senescence by ABT263 in male mice was accompanied by significantly improved performance in the MWM. This study provides compelling evidence that senescence contributes to brain dysfunction after rmTBI, but may do so in a sex-dependent manner.
... Oligodendrocytes form myelin by dramatically rearranging their cell morphology to ensheath and then spirally wrap dozens of individual myelin sheaths around neuronal axons. Central to the ability of an oligodendrocyte to form myelin is its actin cytoskeleton (Brown and Macklin, 2020), which powers morphological changes in two distinct steps: first, actin assembly is required for early stages of myelination in which oligodendrocytes extend their cellular processes to make first contact with axons that they loosely ensheath (Wilson and Brophy, 1989;Zuchero et al., 2015) similar to how actin assembly drives the extension of neuronal growth cones (Fox et al., 2006). Second, and unexpectedly, dramatic disassembly of the oligodendrocyte actin cytoskeleton occurs prior to the start of myelin wrapping (Nawaz et al., 2015;Zuchero et al., 2015). ...
Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.
Highlights
Developmental CNS myelination requires the transcription factor SRF in oligodendrocytes.
SRF targets actin and actin-regulatory but not myelin related genes.
SRF drives oligodendrocyte actin cytoskeleton dynamics during early stages of myelination.
... Myelinating cells of PNS undergo dramatic cytoskeletal reorganization during differentiation and myelination (Brown & Macklin, 2020). In this study, we identified many acetylated myelinrelated proteins, such as MAG, MBP, and MPZ. ...
Lysine acetylation is a reversible post‐translational modification (PTM) involved in multiple physiological functions. Recent studies have demonstrated the involvement of protein acetylation in modulating the biology of Schwann cells (SCs) and regeneration of the peripheral nervous system (PNS). However, the mechanisms underlying these processes remain partially understood. Here, we characterized the acetylome of the mouse sciatic nerve (SN) and investigated the cellular distribution of acetylated proteins. We identified 483 acetylated proteins containing 1442 acetylation modification sites in the SN of adult C57BL/6 mice. Bioinformatics suggested that these acetylated SN proteins were mainly located in the myelin sheath, mitochondrial inner membrane, and cytoskeleton, and highlighted the significant differences between the mouse SN and brain acetylome. Manual annotation further indicated that most acetylated proteins (> 45%) were associated with mitochondria, energy metabolism, and cytoskeleton and cell adhesion. We verified three newly discovered acetylation‐modified proteins, including neurofilament light polypeptide (NEFL), neurofilament medium/high polypeptide (NFM/H), and periaxin (PRX). Immunofluorescence illustrated that the acetylated proteins, including acetylated alpha‐tubulin, were mainly co‐localized with S100‐positive SCs. Herein, we provided a comprehensive acetylome for the mouse SN and demonstrated that acetylated proteins in the SN were predominantly located in SCs. These results will extend our understanding and promote further study of the role and mechanism of protein acetylation in SC development and PNS regeneration. image
... Therefore, we decided to investigate the roles of Tnc and Tnr in a myelin lesion model based on the application of cuprizone to the chow [81,82]. In this approach, the newly formed myelin sheaths are generally thinner and shorter than the former ones [48,83,84]. The effects on myelin formation were monitored by electron microscopy and by examining well-established markers of oligodendrocyte progenitor maturation and the major macroglial cell types. ...
Oligodendrocytes are the myelinating cells of the central nervous system. The physiological importance of oligodendrocytes is highlighted by diseases such as multiple sclerosis, in which the myelin sheaths are degraded and the axonal signal transmission is compromised. In a healthy brain, spontaneous remyelination is rare, and newly formed myelin sheaths are thinner and shorter than the former ones. The myelination process requires the migration, proliferation, and differentiation of oligodendrocyte precursor cells (OPCs) and is influenced by proteins of the extracellular matrix (ECM), which consists of a network of glycoproteins and proteoglycans. In particular, the glycoprotein tenascin-C (Tnc) has an inhibitory effect on the differentiation of OPCs and the remyelination efficiency of oligodendrocytes. The structurally similar tenascin-R (Tnr) exerts an inhibitory influence on the formation of myelin membranes in vitro. When Tnc knockout oligodendrocytes were applied to an in vitro myelination assay using artificial fibers, a higher number of sheaths per single cell were obtained compared to the wild-type control. This effect was enhanced by adding brain-derived neurotrophic factor (BDNF) to the culture system. Tnr−/− oligodendrocytes behaved differently in that the number of formed sheaths per single cell was decreased, indicating that Tnr supports the differentiation of OPCs. In order to study the functions of tenascin proteins in vivo Tnc−/− and Tnr−/− mice were exposed to Cuprizone-induced demyelination for a period of 10 weeks. Both Tnc−/− and Tnr−/− mouse knockout lines displayed a significant increase in the regenerating myelin sheath thickness after Cuprizone treatment. Furthermore, in the absence of either tenascin, the number of OPCs was increased. These results suggest that the fine-tuning of myelin regeneration is regulated by the major tenascin proteins of the CNS.
