Calcium Signaling in the Oligodendrocyte Lineage: Regulators and Consequences.

Cells of the oligodendrocyte lineage express a wide range of Ca2+ channels and receptors that regulate oligodendrocyte progenitor cell (OPC) and oligodendrocyte formation and function. Here we define those key channels and receptors that regulate Ca2+ signaling and OPC development and myelination. We then discuss how the regulation of intracellular Ca2+ in turn affects OPC and oligodendrocyte biology in the healthy nervous system and under pathological conditions. Activation of Ca2+ channels and receptors in OPCs and oligodendrocytes by neurotransmitters converges on regulating intracellular Ca2+, making Ca2+ signaling a central candidate mediator of activity-driven myelination. Indeed, recent evidence indicates that localized changes in Ca2+ in oligodendrocytes can regulate the formation and remodeling of myelin sheaths and perhaps additional functions of oligodendrocytes and OPCs. Thus, decoding how OPCs and myelinating oligodendrocytes integrate and process Ca2+ signals will be important to fully understand central nervous system formation, health, and function.

Neuronal Activity-Dependent Control of Postnatal Neurogenesis and Gliogenesis.

The addition of new neurons and oligodendroglia in the postnatal and adult mammalian brain presents distinct forms of gray and white matter plasticity. Substantial effort has been devoted to understanding the cellular and molecular mechanisms controlling postnatal neurogenesis and gliogenesis, revealing important parallels to principles governing the embryonic stages. While during central nervous system development, scripted temporal and spatial patterns of neural and glial progenitor proliferation and differentiation are necessary to create the nervous system architecture, it remains unclear what driving forces maintain and sustain postnatal neural stem cell (NSC) and oligodendrocyte progenitor cell (OPC) production of new neurons and glia. In recent years, neuronal activity has been identified as an important modulator of these processes. Using the distinct properties of neurotransmitter ionotropic and metabotropic channels to signal downstream cellular events, NSCs and OPCs share common features in their readout of neuronal activity patterns. Here we review the current evidence for neuronal activity-dependent control of NSC/OPC proliferation and differentiation in the postnatal brain, highlight some potential mechanisms used by the two progenitor populations, and discuss future studies that might advance these research areas further.

Myelin basic protein mRNA levels affect myelin sheath dimensions, architecture, plasticity, and density of resident glial cells.

Myelin Basic Protein (MBP) is essential for both elaboration and maintenance of CNS myelin, and its reduced accumulation results in hypomyelination. How different Mbp mRNA levels affect myelin dimensions across the lifespan and how resident glial cells may respond to such changes are unknown. Here, to investigate these questions, we used enhancer-edited mouse lines that accumulate Mbp mRNA levels ranging from 8% to 160% of wild type. In young mice, reduced Mbp mRNA levels resulted in corresponding decreases in Mbp protein accumulation and myelin sheath thickness, confirming the previously demonstrated rate-limiting role of Mbp transcription in the control of initial myelin synthesis. However, despite maintaining lower line specific Mbp mRNA levels into old age, both MBP protein levels and myelin thickness improved or fully normalized at rates defined by the relative Mbp mRNA level. Sheath length, in contrast, was affected only when mRNA levels were very low, demonstrating that sheath thickness and length are not equally coupled to Mbp mRNA level. Striking abnormalities in sheath structure also emerged with reduced mRNA levels. Unexpectedly, an increase in the density of all glial cell types arose in response to reduced Mbp mRNA levels. This investigation extends understanding of the role MBP plays in myelin sheath elaboration, architecture, and plasticity across the mouse lifespan and illuminates a novel axis of glial cell crosstalk.

The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation.

Oligodendrocytes (OLs) are glial cells that ensheath neuronal axons and form myelin in the central nervous system (CNS). OLs are differentiated from oligodendrocyte precursor cells (OPCs) during development and myelin repair, which is often insufficient in the latter case in demyelinating diseases such as multiple sclerosis (MS). Many factors have been reported to regulate OPC-to-OL differentiation, including a number of G protein-coupled receptors (GPCRs). In an effort to search pathways downstream of GPCRs that might be involved in OPC differentiation, we discover that U73122, a phosphoinositide specific phospholipase C (PI-PLC) inhibitor, dramatically promotes OPC-to-OL differentiation and myelin regeneration in experimental autoimmune encephalomyelitis model. Unexpectedly, U73343, a close analog of U73122 which lacks PI-PLC inhibitory activity also promotes OL differentiation, while another reported PI-PLC inhibitor edelfosine does not have such effect, suggesting that U73122 and U73343 enhance OPC differentiation independent of PLC. Although the structures of U73122 and U73343 closely resemble 17ß-estradiol, and both compounds do activate estrogen receptors Erα and Erß with low efficacy and potency, further study indicates that these compounds do not act through Erα and/or Erß to promote OPC differentiation. RNA-Seq and bioinformatic analysis indicate that U73122 and U73343 may regulate cholesterol biosynthesis. Further study shows both compounds increase 14-dehydrozymostenol, a steroid reported to promote OPC differentiation, in OPC culture. In conclusion, the aminosteroids U73122 and U73343 promote OPC-to-OL generation and myelin formation by regulating cholesterol biosynthesis pathway.

Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation.

Oligodendrocytes (OLs) are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). Demyelination is a common feature of many neurological diseases such as multiple sclerosis (MS) and leukodystrophies. Although spontaneous remyelination can happen after myelin injury, nevertheless, it is often insufficient and may lead to aggravated neurodegeneration and neurological disabilities. Our previous study has discovered that MEK/ERK pathway negatively regulates OPC-to-OL differentiation and remyelination in mouse models. To facilitate possible clinical evaluation, here we investigate several MEK inhibitors which have been approved by FDA for cancer therapies in both mouse and human OPC-to-OL differentiation systems. Trametinib, the first FDA approved MEK inhibitor, displays the best effect in stimulating OL generation in vitro among the four MEK inhibitors examined. Trametinib also significantly enhances remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model. More exciting, trametinib facilitates the generation of MBP+ OLs from human embryonic stem cells (ESCs)-derived OPCs. Mechanism study indicates that trametinib promotes OL generation by reducing E2F1 nuclear translocation and subsequent transcriptional activity. In summary, our studies indicate a similar inhibitory role of MEK/ERK in human and mouse OL generation. Targeting the MEK/ERK pathway might help to develop new therapies or repurpose existing drugs for demyelinating diseases.

Oligodendrocyte progenitor cell recruitment and remyelination in multiple sclerosis: the more, the merrier?

Promoting remyelination to prevent/reduce neurodegeneration in patients with multiple sclerosis (MS) is a major therapeutic goal. The longstanding view that the block of oligodendrocyte progenitor cell (OPC) differentiation in MS lesions is the leading cause of remyelination failure has inspired the scientific community to focus primarily on OPC differentiation-promoting compounds as pro-remyelinating agents. Yet, these strategies have been challenged by findings that active MS lesions contain surviving oligodendrocytes that may contribute to remyelination, while many chronic lesions contain low numbers of oligodendroglial cells. In addition, clinical trials using differentiation-stimulating drugs have shown limited efficacy. Thus, a strategic shift in the design of potential remyelination-promoting therapies may be required to achieve significant clinical benefits, which calls for a careful reconsideration of the mechanisms underlying remyelination failure in MS. Here, we argue that both the rate and the efficacy of OPC recruitment are fundamental determinants of remyelination, and that stimulating this process in MS may be crucial to achieve myelin regeneration. We first review different types of MS lesions in early and chronic MS, with a particular focus on OPCs and surviving oligodendrocytes. Based on the neuropathological findings and results obtained using models of demyelination, we make the case that OPC differentiation block in chronic MS is likely the consequence of defective OPC recruitment during earlier phases of the disease, because (i) if the recruitment is too slow, OPCs reach the axons after what we define as 'remyelination-permissive window', and thus remain undifferentiated; and (ii) if the recruitment is inefficient, OPC density in the lesions remains below the threshold required for differentiation. Importantly, we highlight that OPC proliferation in MS lesions is scarce, which strongly suggests that repeated episodes of demyelination/remyelination (OPC differentiation) will deplete the lesional OPC pool unless perilesional OPCs are recruited. We also point out that surviving mature oligodendrocytes in a subtype of early MS lesions may actually prevent the recruitment of OPCs. Because it has been suggested that OPC-mediated remyelination may be more efficient than that by surviving oligodendrocytes, we suggest that stimulating OPC recruitment during active disease should benefit remyelination in multiple types of lesions, including those with spared oligodendrocytes. Finally, we review molecular determinants of OPC recruitment and suggest a potential therapeutically-relevant strategy to increase this process in patients with MS.

Glutamate Signaling via the AMPAR Subunit GluR4 Regulates Oligodendrocyte Progenitor Cell Migration in the Developing Spinal Cord.

Oligodendrocyte progenitor cells (OPCs) are specified from discrete precursor populations during gliogenesis and migrate extensively from their origins, ultimately distributing throughout the brain and spinal cord during early development. Subsequently, a subset of OPCs differentiates into mature oligodendrocytes, which myelinate axons. This process is necessary for efficient neuronal signaling and organism survival. Previous studies have identified several factors that influence OPC development, including excitatory glutamatergic synapses that form between neurons and OPCs during myelination. However, little is known about how glutamate signaling affects OPC migration before myelination. In this study, we use in vivo, time-lapse imaging in zebrafish in conjunction with genetic and pharmacological perturbation to investigate OPC migration and myelination when the GluR4A ionotropic glutamate receptor subunit is disrupted. In our studies, we observed that gria4a mutant embryos and larvae displayed abnormal OPC migration and altered dorsoventral distribution in the spinal cord. Genetic mosaic analysis confirmed that these effects were cell-autonomous, and we identified that voltage-gated calcium channels were downstream of glutamate receptor signaling in OPCs and could rescue the migration and myelination defects we observed when glutamate signaling was perturbed. These results offer new insights into the complex system of neuron-OPC interactions and reveal a cell-autonomous role for glutamatergic signaling in OPCs during neural development.SIGNIFICANCE STATEMENT The migration of oligodendrocyte progenitor cells (OPCs) is an essential process during development that leads to uniform oligodendrocyte distribution and sufficient myelination for central nervous system function. Here, we demonstrate that the AMPA receptor (AMPAR) subunit GluR4A is an important driver of OPC migration and myelination in vivo and that activated voltage-gated calcium channels are downstream of glutamate receptor signaling in mediating this migration.

A role for sustained MAPK activity in the mouse ventral telencephalon.

The MAPK pathway is a major growth signal that has been implicated during the development of progenitors, neurons, and glia in the embryonic brain. Here, we show that the MAPK pathway plays an important role in the generation of distinct cell types from progenitors in the ventral telencephalon. Our data reveal that phospho-p44/42 (called p-ERK1/2) and the ETS transcription factor Etv5, both downstream effectors in the MAPK pathway, show a regional bias in expression during ventral telencephalic development, with enriched expression in the dorsal region of the LGE and ventral region of the MGE at E13.5 and E15.5. Interestingly, expression of both factors becomes more uniform in ventricular zone (VZ) progenitors by E18.5. To gain insight into the role of MAPK activity during progenitor cell development, we used a cre inducible constitutively active MEK1 allele (RosaMEK1DD/+) in combination with a ventral telencephalon enriched cre (Gsx2e-cre) or a dorsal telencephalon enriched cre (Emx1cre/+). Sustained MEK/MAPK activity in the ventral telencephalon (Gsx2e-cre; RosaMEK1DD/+) expanded dorsal lateral ganglionic eminence (dLGE) enriched genes (Gsx2 and Sp8) and oligodendrocyte progenitor cell (OPC) markers (Olig2, Pdgfrα, and Sox10), and also reduced markers in the ventral (v) LGE domain (Isl1 and Foxp1). Activation of MEK/MAPK activity in the dorsal telencephalon (Emx1cre/+; RosaMEK1DD/+) did not initially activate the expression of dLGE or OPC genes at E15.5 but ectopic expression of Gsx2 and OPC markers were observed at E18.5. These results support the idea that MAPK activity as readout by p-ERK1/2 and Etv5 expression is enriched in distinct subdomains of ventral telencephalic progenitors during development. In addition, sustained activation of the MEK/MAPK pathway in the ventral or dorsal telencephalon influences dLGE and OPC identity from progenitors.

The orphan G protein-coupled receptor GPR149 is a negative regulator of myelination and remyelination.

Myelin sheath, formed by oligodendrocytes (OLs) in the central nervous system (CNS) and Schwann cells in periphery, plays a critical role in supporting neuronal functions. OLs, differentiated from oligodendrocyte precursor cells (OPCs), are important for myelination during development and myelin repair in CNS demyelinating disease. To identify mechanisms of myelin development and remyelination after myelin damage is of great clinical interest. Here we show that the orphan G protein-coupled receptor GPR149, enriched in OPCs, negatively regulate OPC to OL differentiation, myelination, as well as remyelination. The expression of GPR149 is downregulated during OPCs differentiation into OLs. GPR149 deficiency does not affect the number of OPCs, but promotes OPC to OL differentiation which results in earlier development of myelin. In cuprizone-induced demyelination model, GPR149 deficiency significantly enhances myelin regeneration. Further study indicates that GPR149 may regulate OL differentiation and myelin formation via MAPK/ERK pathway. Our study suggests that deleting or blocking GPR149 might be an intriguing way to promote myelin repair in demyelinating diseases.

The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination.

The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated demyelination, as occurs in multiple sclerosis. However, remyelination-the regeneration of myelin sheaths-also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that the inflammatory response during CNS remyelination in mice is modulated by antibiotic or probiotic treatment, as well as in germ-free mice. We also explore the effect of these changes on oligodendrocyte progenitor cell differentiation, which is inhibited by antibiotics but unaffected by our other interventions. These results reveal that high combined doses of oral antibiotics impair oligodendrocyte progenitor cell responses during remyelination and further our understanding of how mammalian regeneration relates to the microbiota.

The Secreted Glycoprotein Reelin Suppresses the Proliferation and Regulates the Distribution of Oligodendrocyte Progenitor Cells in the Embryonic Neocortex.

Oligodendrocyte (OL) progenitor cells (OPCs) are generated, proliferate, migrate, and differentiate in the developing brain. Although the development of OPCs is prerequisite for normal brain function, the molecular mechanisms regulating their development in the neocortex are not fully understood. Several molecules regulate the tangential distribution of OPCs in the developing neocortex, but the cue molecule(s) that regulate their radial distribution remains unknown. Here, we demonstrate that the secreted glycoprotein Reelin suppresses the proliferation of OPCs and acts as a repellent for their migration in vitro These functions rely on the binding of Reelin to its receptors and on the signal transduction involving the intracellular protein Dab1. In the late embryonic neocortex of mice with attenuated Reelin signaling [i.e., Reelin heterozygote-deficient, Dab1 heterozygote-deficient mutant, or very low-density lipoprotein receptor (VLDLR)-deficient mice], the number of OPCs increased and their distribution shifted toward the superficial layers. In contrast, the number of OPCs decreased and they tended to distribute in the deep layers in the neocortex of mice with abrogated inactivation of Reelin by proteolytic cleavage, namely a disintegrin and metalloproteinase with thrombospondin type 1 motifs 3 (ADAMTS-3)-deficient mice and cleavage-resistant Reelin knock-in mice. Both male and female animals were used. These data indicate that Reelin-Dab1 signaling regulates the proliferation and radial distribution of OPCs in the late embryonic neocortex and that the regulation of Reelin function by its specific proteolysis is required for the normal development of OPCs.SIGNIFICANCE STATEMENT Here, we report that Reelin-Dab1 signaling regulates the proliferation and radial distribution of OPCs in the late embryonic mouse neocortex. Oligodendrocyte (OL) progenitor cells (OPCs) express Reelin signaling molecules and respond to Reelin stimulation. Reelin-Dab1 signaling suppresses the proliferation of OPCs both in vitro and in vivo Reelin repels OPCs in vitro, and the radial distribution of OPCs is altered in mice with either attenuated or augmented Reelin-Dab1 signaling. This is the first report identifying the secreted molecule that plays a role in the radial distribution of OPCs in the late embryonic neocortex. Our results also show that the regulation of Reelin function by its specific proteolysis is important for the normal development of OPCs.

MiRNA-145-5p prevents differentiation of oligodendrocyte progenitor cells by regulating expression of myelin gene regulatory factor.

The roles of specific microRNAs (miRNA) in oligodendrocyte (OL) differentiation have been studied in depth. However, miRNAs in OL precursors and oligodendrocyte progenitor cells (OPCs) have been less extensively investigated. MiR-145-5p is highly expressed in OPCs relative to differentiating OLs, suggesting this miRNA may serve a function specifically in OPCs. Knockdown of miR-145-5p in primary OPCs led to spontaneous differentiation, as evidenced by an increased proportion of MAG+ cells, increased cell ramification, and upregulation of multiple myelin genes including MYRF, TPPP, and MAG, and OL cell cycle exit marker Cdkn1c. Supporting this transition to a differentiating state, proliferation was reduced in miR-145-5p knockdown OPCs. Further, knockdown of miR-145-5p in differentiating OLs showed enhanced differentiation, with increased branching, myelin membrane production, and myelin gene expression. We identified several OL-specific genes targeted by miR-145-5p that exhibited upregulation with miR-145-5p knockdown, including myelin gene regulatory factor (MYRF), that could be regulating the prodifferentiation phenotype in both miR-145 knockdown OPCs and OLs. Indeed, spontaneous differentiation with knockdown of miR-145-5p was fully rescued by concurrent knockdown of MYRF. However, proliferation rate was only partially rescued with MYRF knockdown, and overexpression of miR-145-5p in OPCs increased proliferation rate without affecting expression of already lowly expressed differentiation genes. Taken together, these data suggest that in OPCs miR-145-5p both prevents differentiation at least in part by preventing expression of MYRF and promotes proliferation via as-yet-unidentified mechanisms. These findings clarify the need for differential regulation of miR-145-5p between OPCs and OLs and may have further implications in demyelinating diseases such as multiple sclerosis where miR-145-5p is dysregulated.

Kif3a deletion prevents primary cilia assembly on oligodendrocyte progenitor cells, reduces oligodendrogenesis and impairs fine motor function.

Primary cilia are small microtubule-based organelles capable of transducing signals from growth factor receptors embedded in the cilia membrane. Developmentally, oligodendrocyte progenitor cells (OPCs) express genes associated with primary cilia assembly, disassembly, and signaling, however, the importance of primary cilia for adult myelination has not been explored. We show that OPCs are ciliated in vitro and in vivo, and that they disassemble their primary cilia as they progress through the cell cycle. OPC primary cilia are also disassembled as OPCs differentiate into oligodendrocytes. When kinesin family member 3a (Kif3a), a gene critical for primary cilium assembly, was conditionally deleted from adult OPCs in vivo (Pdgfrα-CreER™:: Kif3a fl/fl transgenic mice), OPCs failed to assemble primary cilia. Kif3a-deletion was also associated with reduced OPC proliferation and oligodendrogenesis in the corpus callosum and motor cortex and a progressive impairment of fine motor coordination.

The synaptic blocker botulinum toxin A decreases the density and complexity of oligodendrocyte precursor cells in the adult mouse hippocampus.

Oligodendrocyte progenitor cells (OPCs) are responsible for generating oligodendrocytes, the myelinating cells of the CNS. Life-long myelination is promoted by neuronal activity and is essential for neural network plasticity and learning. OPCs are known to contact synapses and it is proposed that neuronal synaptic activity in turn regulates their behavior. To examine this in the adult, we performed unilateral injection of the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of adult mice. We confirm BoNT/A cleaves SNAP-25 in the CA1 are of the hippocampus, which has been proven to block neurotransmission. Notably, BoNT/A significantly decreased OPC density and caused their shrinkage, as determined by immunolabeling for the OPC marker NG2. Furthermore, BoNT/A resulted in an overall decrease in the number of OPC processes, as well as a decrease in their lengths and branching frequency. These data indicate that synaptic activity is important for maintaining adult OPC numbers and cellular integrity, which is relevant to pathophysiological scenarios characterized by dysregulation of synaptic activity, such as age-related cognitive decline, Multiple Sclerosis and Alzheimer's disease.

Function and Mechanism of Myelin Regulation in Alcohol Abuse and Alcoholism.

Excessive alcohol use has adverse effects on the central nervous system (CNS) and can lead to alcohol use disorders (AUDs). Recent studies have suggested that myelin reductions may directly contribute to CNS dysfunctions associated with AUDs. Myelin consists of compact lipid membranes wrapped around axons to provide electrical insulation and trophic support. Regulation of myelin is considered as a new form of neural plasticity due to its profound impacts on the computation of neural networks. In this review, the authors first discuss experimental evidence showing how alcohol exposure causes demyelination in different brain regions, often accompanied by deficits in cognition and emotion. Next, they discuss postulated molecular and cellular mechanisms underlying alcohol's impact on myelin. It is clear that more extensive investigations are needed in this important but underexplored research field in order to gain a better understanding of the myelin-behavior relationship and to develop new treatment strategies for AUDs.

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury.

Oligodendrocyte progenitor cells (OPCs) are the most proliferative and dispersed population of progenitor cells in the adult central nervous system, which allows these cells to rapidly respond to damage. Oligodendrocytes and myelin are lost after traumatic spinal cord injury (SCI), compromising efficient conduction and, potentially, the long-term health of axons. In response, OPCs proliferate and then differentiate into new oligodendrocytes and Schwann cells to remyelinate axons. This culminates in highly efficient remyelination following experimental SCI in which nearly all intact demyelinated axons are remyelinated in rodent models. However, myelin regeneration comprises only one role of OPCs following SCI. OPCs contribute to scar formation after SCI and restrict the regeneration of injured axons. Moreover, OPCs alter their gene expression following demyelination, express cytokines and perpetuate the immune response. Here, we review the functional contribution of myelin regeneration and other recently uncovered roles of OPCs and their progeny to repair following SCI.

Possible regenerative effects of fingolimod (FTY720) in multiple sclerosis disease: An overview on remyelination process.

Fingolimod (FTY720) is a sphingosine 1-phosphate (S1P) receptor analog, which has been approved as an oral immunomodulator for treating relapsing-remitting multiple sclerosis. This drug prevents lymphocyte egression from lymph nodes and reduces the infiltration of inflammatory mediators into the central nervous system. Based on its lipophilic nature, FTY720 passes through the blood-brain barrier and can directly affect neural cells. A notably different subtype of S1P receptors expresses in neural cells, which suggests FTY720 is a drug capable of affecting neural cells. Oligodendrocytes (OLs) are considered as the primary target cells in MS. Remyelination is a process including the proliferation of neural progenitors and oligodendrocyte precursor cells, their migration to the lesion site and their differentiation to mature oligodendrocytes. Experimental and clinical studies have described the impact of FTY720 on endogenous remyelination elements. In this review, we will explain the current clinical and experimental evidence that exists on the effects of FTY720 on remyelination and the underlying mechanisms.

Design, synthesis, and biological evaluation of spiroindolines as novel inducers of oligodendrocyte progenitor cell differentiation-Use of a conformation-based hypothesis to facilitate compound design.

Inducing oligodendrocyte progenitor cell (OPC) differentiation is a novel therapeutic strategy for the treatment of demyelinating diseases such as multiple sclerosis (MS). In the preceding article, we detailed the discovery of compound 1, a potent inducer of OPC differentiation possessing a characteristic spiroindoline structure. Also, we found that N-methylation and des-carbonyl compound 1 (4) led to a loss in potency. Herein, we describe our investigations of a conformation-based hypothesis for OPC differentiation activity based on the preferred conformation of the spiro core, and further structure-activity relationship (SAR) exploration led to the identification of 6-CF3 derivative 8, which was more potent compared to compound 1.

Oligodendrocyte Progenitor Cells in the Tumor Microenvironment.

Glioblastoma (GBM) develops from adult brain white matter and is the most common and lethal primary brain tumor, characterized by rapid growth and invasion. GBM tumors frequently spread into the contralateral hemisphere, including in the beginning of tumor development. However, after complete resection of the tumor mass and chemo-radiotherapy, GBM commonly recurs around the tumor removal site, suggesting that the microenvironment at the tumor border provides therapeutic resistance to GBM cells. To improve patient prognosis, understanding the microenvironment at the tumor border is critical. Several microRNAs (miRNAs) show higher expression at the tumor border, with the top three involved in oligodendrocyte differentiation. Oligodendrocyte progenitor cells (OPCs) may induce stemness and chemo-radioresistance in GBM cells, providing a supportive function to promote GBM. This review describes important features of OPCs and insights into the "border niche," a unique microenvironment that allows GBM cells to survive and recur at the tumor border.

R-Ras1 and R-Ras2 Are Essential for Oligodendrocyte Differentiation and Survival for Correct Myelination in the Central Nervous System.

Rapid and effective neural transmission of information requires correct axonal myelination. Modifications in myelination alter axonal capacity to transmit electric impulses and enable pathological conditions. In the CNS, oligodendrocytes (OLs) myelinate axons, a complex process involving various cellular interactions. However, we know little about the mechanisms that orchestrate correct myelination. Here, we demonstrate that OLs express R-Ras1 and R-Ras2. Using female and male mutant mice to delete these proteins, we found that activation of the PI3K/Akt and Erk1/2-MAPK pathways was weaker in mice lacking one or both of these GTPases, suggesting that both proteins coordinate the activity of these two pathways. Loss of R-Ras1 and/or R-Ras2 diminishes the number of OLs in major myelinated CNS tracts and increases the proportion of immature OLs. In R-Ras1-/- and R-Ras2-/--null mice, OLs show aberrant morphologies and fail to differentiate correctly into myelin-forming phenotypes. The smaller OL population and abnormal OL maturation induce severe hypomyelination, with shorter nodes of Ranvier in R-Ras1-/- and/or R-Ras2-/- mice. These defects explain the slower conduction velocity of myelinated axons that we observed in the absence of R-Ras1 and R-Ras2. Together, these results suggest that R-Ras1 and R-Ras2 are upstream elements that regulate the survival and differentiation of progenitors into OLs through the PI3K/Akt and Erk1/2-MAPK pathways for proper myelination.SIGNIFICANCE STATEMENT In this study, we show that R-Ras1 and R-Ras2 play essential roles in regulating myelination in vivo and control fundamental aspects of oligodendrocyte (OL) survival and differentiation through synergistic activation of PI3K/Akt and Erk1/2-MAPK signaling. Mice lacking R-Ras1 and/or R-Ras2 show a diminished OL population with a higher proportion of immature OLs, explaining the observed hypomyelination in main CNS tracts. In vivo electrophysiology recordings demonstrate a slower conduction velocity of nerve impulses in the absence of R-Ras1 and R-Ras2. Therefore, R-Ras1 and R-Ras2 are essential for proper axonal myelination and accurate neural transmission.