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The central dogma in remyelination states that the primary cellular source for myelin repair are the oligodendrocyte precursor cells. In this issue of Neuron, Mezydlo et al. 1 highlight the potential of preexisting oligodendrocytes as an alternative, albeit minor, source for new myelin, with implications for demyelinating disorder research and therapies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Oligodendrocyte precursor cells (OPCs) use the vasculature as a scaffold for their migration. In this issue of Neuron, Su et al. determine that astrocytic ensheathment of the vasculature mediates OPC detachment from blood vessels via the secretion of semaphorins, regulating the timing of oligodendrocyte differentiation., Competing Interests: Declaration of interests B.E. is a founder of and has received consulting fees from Autobahn Therapeutics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Microglia have emerged as essential regulators of neurodevelopment by phagocytosing synapses. Recently, we showed that microglia engulf viable oligodendrocyte progenitor cells (OPCs) during development to facilitate myelination. Here, we describe a protocol to quantify microglial engulfment of whole cells using 3D confocal microscopy to differentiate microglial contact. This protocol can be applied to assess whole-cell engulfment in a variety of contexts and cell types. For complete details on the use and execution of this protocol, please refer to Nemes-Baran et al. (2020)., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

The molecular mechanisms that govern the maturation of oligodendrocyte lineage cells remain unclear. Emerging studies have shown that N 6 -methyladenosine (m 6 A), the most common internal RNA modification of mammalian mRNA, plays a critical role in various developmental processes. Here, we demonstrate that oligodendrocyte lineage progression is accompanied by dynamic changes in m 6 A modification on numerous transcripts. In vivo conditional inactivation of an essential m 6 A writer component, METTL14, results in decreased oligodendrocyte numbers and CNS hypomyelination, although oligodendrocyte precursor cell (OPC) numbers are normal. In vitro Mettl14 ablation disrupts postmitotic oligodendrocyte maturation and has distinct effects on OPC and oligodendrocyte transcriptomes. Moreover, the loss of Mettl14 in oligodendrocyte lineage cells causes aberrant splicing of myriad RNA transcripts, including those that encode the essential paranodal component neurofascin 155 (NF155). Together, our findings indicate that dynamic RNA methylation plays an important regulatory role in oligodendrocyte development and CNS myelination., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Sox17, a SoxF family member transiently upregulated during postnatal oligodendrocyte (OL) development, promotes OL cell differentiation, but its function in white matter development and pathology in vivo is unknown. Our analysis of oligodendroglial- and OL-progenitor-cell-targeted ablation in vivo using a floxed Sox17 mouse establishes a dependence of postnatal oligodendrogenesis on Sox17 and reveals Notch signaling as a mediator of Sox17 function. Following Sox17 ablation, reduced numbers of Olig2-expressing cells and mature OLs led to developmental hypomyelination and motor dysfunction. After demyelination, Sox17 deficiency inhibited OL regeneration. OL decline was unexpectedly preceded by transiently increased differentiation and a reduction of OL progenitor cells. Evidence of a dual role for Sox17 in progenitor cell expansion by Notch and differentiation involving TCF7L2 expression were found. A program of progenitor expansion and differentiation promoted by Sox17 through Notch thus contributes to OL production and determines the outcome of white matter repair., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS). Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases. Here, we show that the differentiation potential of adult rodent OPCs decreases with age. Aged OPCs become unresponsive to pro-differentiation signals, suggesting intrinsic constraints on therapeutic approaches aimed at enhancing OPC differentiation. This decline in functional capacity is associated with hallmarks of cellular aging, including decreased metabolic function and increased DNA damage. Fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following focal demyelination. Aged OPCs treated with metformin regain responsiveness to pro-differentiation signals, suggesting synergistic effects of rejuvenation and pro-differentiation therapies. These findings provide insight into aging-associated remyelination failure and suggest therapeutic interventions for reversing such declines in chronic disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The initiation of axoglial contact is considered a prerequisite for myelination, yet the role cell adhesion molecules (CAMs) play in mediating such interactions remains unclear. To examine the function of axoglial CAMs, we tested whether enhanced CAM-mediated adhesion between OLs and neurons could affect myelination. Here we show that increased expression of a membrane-bound extracellular domain of Cadm4 (Cadm4dCT) in cultured oligodendrocytes results in the production of numerous axoglial contact sites that fail to elongate and generate mature myelin. Transgenic mice expressing Cadm4dCT were hypomyelinated and exhibit multiple myelin abnormalities, including myelination of neuronal somata. These abnormalities depend on specific neuron-glial interaction as they were not observed when these OLs were cultured alone, on nanofibers, or on neurons isolated from mice lacking the axonal receptors of Cadm4. Our results demonstrate that tightly regulated axon-glia adhesion is essential for proper myelin targeting and subsequent membrane wrapping and lateral extension., (Copyright © 2018 Elsevier Inc. All rights reserved.)