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Neuron Dec 2020Myelination facilitates rapid axonal conduction, enabling efficient communication across different parts of the nervous system. Here we examined mechanisms controlling...
Myelination facilitates rapid axonal conduction, enabling efficient communication across different parts of the nervous system. Here we examined mechanisms controlling myelination after injury and during axon regeneration in the central nervous system (CNS). Previously, we discovered multiple molecular pathways and strategies that could promote robust axon regrowth after optic nerve injury. However, regenerated axons remain unmyelinated, and the underlying mechanisms are elusive. In this study, we found that, in injured optic nerves, oligodendrocyte precursor cells (OPCs) undergo transient proliferation but fail to differentiate into mature myelination-competent oligodendrocytes, reminiscent of what is observed in human progressive multiple sclerosis. Mechanistically, we showed that OPC-intrinsic GPR17 signaling and sustained activation of microglia inhibit different stages of OPC differentiation. Importantly, co-manipulation of GPR17 and microglia led to extensive myelination of regenerated axons. The regulatory mechanisms of stage-dependent OPC differentiation uncovered here suggest a translatable strategy for efficient de novo myelination after CNS injury.
Topics: Animals; Axons; Cell Differentiation; Cell Proliferation; Female; Male; Mice; Mice, Transgenic; Microglia; Myelin Sheath; Nerve Fibers, Myelinated; Nerve Regeneration; Nerve Tissue Proteins; Oligodendrocyte Precursor Cells; Random Allocation; Receptors, G-Protein-Coupled
PubMed: 33108748
DOI: 10.1016/j.neuron.2020.09.016 -
Glia Dec 2022Myelin is essential to nervous system function, playing roles in saltatory conduction and trophic support. Oligodendrocytes (OLs) and Schwann cells (SCs) form myelin in... (Review)
Review
Myelin is essential to nervous system function, playing roles in saltatory conduction and trophic support. Oligodendrocytes (OLs) and Schwann cells (SCs) form myelin in the central and peripheral nervous systems respectively and follow different developmental paths. OLs are neural stem-cell derived and follow an intrinsic developmental program resulting in a largely irreversible differentiation state. During embryonic development, OL precursor cells (OPCs) are produced in distinct waves originating from different locations in the central nervous system, with a subset developing into myelinating OLs. OPCs remain evenly distributed throughout life, providing a population of responsive, multifunctional cells with the capacity to remyelinate after injury. SCs derive from the neural crest, are highly dependent on extrinsic signals, and have plastic differentiation states. SC precursors (SCPs) are produced in early embryonic nerve structures and differentiate into multipotent immature SCs (iSCs), which initiate radial sorting and differentiate into myelinating and non-myelinating SCs. Differentiated SCs retain the capacity to radically change phenotypes in response to external signals, including becoming repair SCs, which drive peripheral regeneration. While several transcription factors and myelin components are common between OLs and SCs, their differentiation mechanisms are highly distinct, owing to their unique lineages and their respective environments. In addition, both OLs and SCs respond to neuronal activity and regulate nervous system output in reciprocal manners, possibly through different pathways. Here, we outline their basic developmental programs, mechanisms regulating their differentiation, and recent advances in the field.
Topics: Female; Humans; Myelin Sheath; Neuroglia; Peripheral Nervous System; Pregnancy; Schwann Cells; Transcription Factors
PubMed: 35785432
DOI: 10.1002/glia.24238 -
Developmental Cell Jul 2021Developmental myelination is a protracted process that extends well into postnatal life. Cell-intrinsic mechanisms operate in myelin-forming oligodendrocytes, as well as... (Review)
Review
Developmental myelination is a protracted process that extends well into postnatal life. Cell-intrinsic mechanisms operate in myelin-forming oligodendrocytes, as well as microenvironmental interactions that guide and modulate every aspect of myelination, from oligodendrocyte precursor cell migration to oligodendrocyte differentiation and the formation of stable myelin internodes. During development and throughout adult life, neuron-oligodendroglial interactions shape activity and experience-dependent myelin adaptations to fine-tune neural circuit dynamics and promote healthy neurological function.
Topics: Cell Differentiation; Cell Movement; Cellular Microenvironment; Humans; Myelin Sheath; Neurons; Oligodendroglia
PubMed: 34192527
DOI: 10.1016/j.devcel.2021.06.006 -
Neuroscience Sep 2014Studying how the healthy human brain develops is important to understand early pathological mechanisms and to assess the influence of fetal or perinatal events on later... (Review)
Review
Studying how the healthy human brain develops is important to understand early pathological mechanisms and to assess the influence of fetal or perinatal events on later life. Brain development relies on complex and intermingled mechanisms especially during gestation and first post-natal months, with intense interactions between genetic, epigenetic and environmental factors. Although the baby's brain is organized early on, it is not a miniature adult brain: regional brain changes are asynchronous and protracted, i.e. sensory-motor regions develop early and quickly, whereas associative regions develop later and slowly over decades. Concurrently, the infant/child gradually achieves new performances, but how brain maturation relates to changes in behavior is poorly understood, requiring non-invasive in vivo imaging studies such as magnetic resonance imaging (MRI). Two main processes of early white matter development are reviewed: (1) establishment of connections between brain regions within functional networks, leading to adult-like organization during the last trimester of gestation, (2) maturation (myelination) of these connections during infancy to provide efficient transfers of information. Current knowledge from post-mortem descriptions and in vivo MRI studies is summed up, focusing on T1- and T2-weighted imaging, diffusion tensor imaging, and quantitative mapping of T1/T2 relaxation times, myelin water fraction and magnetization transfer ratio.
Topics: Brain; Diffusion Tensor Imaging; Fetus; Humans; Infant; Infant, Newborn; Magnetic Resonance Imaging; Myelin Sheath; White Matter
PubMed: 24378955
DOI: 10.1016/j.neuroscience.2013.12.044 -
Glia Apr 2018Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is... (Review)
Review
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.
Topics: Animals; Humans; Myelin Sheath; TOR Serine-Threonine Kinases
PubMed: 29210103
DOI: 10.1002/glia.23273 -
Cell Sep 2019Microtubules are critical for the extension of oligodendrocyte processes and myelin deposition, yet our knowledge of their microtubule biogenesis is limited. In this...
Microtubules are critical for the extension of oligodendrocyte processes and myelin deposition, yet our knowledge of their microtubule biogenesis is limited. In this issue of Cell, Fu et al. (2019) identify an oligodendrocyte-enriched microtubule regulator that promotes microtubule growth from Golgi outposts and controls myelin sheath elongation, linking microtubule cytoarchitecture and myelination in the CNS.
Topics: Microtubules; Myelin Sheath; Oligodendroglia
PubMed: 31522889
DOI: 10.1016/j.cell.2019.08.046 -
Molecular Metabolism Mar 2023Oligodendrocyte progenitor cell differentiation is regulated by nutritional signals in the adult median eminence (ME), but the consequences on local myelination are...
OBJECTIVE
Oligodendrocyte progenitor cell differentiation is regulated by nutritional signals in the adult median eminence (ME), but the consequences on local myelination are unknown. The aim of this study was to characterize myelin plasticity in the ME of adult mice in health or in response to chronic nutritional challenge and determine its relevance to the regulation of energy balance.
METHODS
We assessed new oligodendrocyte (OL) and myelin generation and stability in the ME of healthy adult male mice using bromodeoxyuridine labelling and genetic fate mapping tools. We evaluated the contribution of microglia to ME myelin plasticity in PLX5622-treated C57BL/6J mice and in Pdgfra-Cre/ER;R26R-eYFP;Myrf mice, where adult oligodendrogenesis is blunted. Next, we investigated how high-fat feeding or caloric restriction impact ME OL lineage progression and myelination. Finally, we characterized the functional relevance of adult oligodendrogenesis on energy balance regulation.
RESULTS
We show that myelinating OLs are continuously and rapidly generated in the adult ME. Paradoxically, OL number and myelin amounts remain remarkably stable in the adult ME. In fact, the high rate of new OL and myelin generation in the ME is offset by continuous turnover of both. We show that microglia are required for continuous OL and myelin production, and that ME myelin plasticity regulates the recruitment of local immune cells. Finally, we provide evidence that ME myelination is regulated by the body's energetic status and demonstrate that ME OL and myelin plasticity are required for the regulation of energy balance and hypothalamic leptin sensitivity.
CONCLUSIONS
This study identifies a new mechanism modulating leptin sensitivity and the central control of energy balance and uncovers a previously unappreciated form of structural plasticity in the ME.
Topics: Mice; Male; Animals; Myelin Sheath; Leptin; Mice, Transgenic; Median Eminence; Mice, Inbred C57BL
PubMed: 36739968
DOI: 10.1016/j.molmet.2023.101690 -
Acta Neuropathologica Communications Mar 2023Alzheimer's disease (AD) is a neurodegenerative disorder with neuronal and synaptic losses due to the accumulation of toxic amyloid β (Αβ) peptide oligomers, plaques,... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disorder with neuronal and synaptic losses due to the accumulation of toxic amyloid β (Αβ) peptide oligomers, plaques, and tangles containing tau (tubulin-associated unit) protein. While familial AD is caused by specific mutations, the sporadic disease is more common and appears to result from a complex chronic brain neuroinflammation with mitochondriopathies, inducing free radicals' accumulation. In aged brain, mutations in DNA and several unfolded proteins participate in a chronic amyloidosis response with a toxic effect on myelin sheath and axons, leading to cognitive deficits and dementia. Αβ peptides are the most frequent form of toxic amyloid oligomers. Accumulations of misfolded proteins during several years alters different metabolic mechanisms, induce chronic inflammatory and immune responses with toxic consequences on neuronal cells. Myelin composition and architecture may appear to be an early target for the toxic activity of Aβ peptides and others hydrophobic misfolded proteins. In this work, we describe the possible role of early myelin alterations in the genesis of neuronal alterations and the onset of symptomatology. We propose that some pathophysiological and clinical forms of the disease may arise from structural and metabolic disorders in the processes of myelination/demyelination of brain regions where the accumulation of non-functional toxic proteins is important. In these forms, the primacy of the deleterious role of amyloid peptides would be a matter of questioning and the initiating role of neuropathology would be primarily the fact of dysmyelination.
Topics: Humans; Aged; Alzheimer Disease; Amyloid beta-Peptides; Myelin Sheath; Axons; Neurons
PubMed: 37004127
DOI: 10.1186/s40478-023-01554-5 -
Neurochemical Research Mar 2020Myelinating cells of both the peripheral and central nervous systems (CNSs) undergo dramatic cytoskeletal reorganization in order to differentiate and produce myelin.... (Review)
Review
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 early cell differentiation and that actin depolymerization drives myelin wrapping. Dysregulation of the actin cytoskeleton in myelinating cells is seen in some disease states. This review highlights the cytoskeletal molecules that regulate differentiation of and myelination by cells of the PNS and CNS, informing our understanding of neural development, in particular myelination.
Topics: Actin Cytoskeleton; Animals; Cell Differentiation; Central Nervous System; Humans; Myelin Sheath; Oligodendroglia
PubMed: 30847860
DOI: 10.1007/s11064-019-02753-0 -
Glia Aug 2020Oligodendrocytes, the myelinating cells in the vertebrate central nervous system, produce myelin sheaths to enable saltatory propagation of action potentials. The... (Review)
Review
Oligodendrocytes, the myelinating cells in the vertebrate central nervous system, produce myelin sheaths to enable saltatory propagation of action potentials. The process of oligodendrocyte myelination entails a stepwise progression from precursor specification to differentiation, which is coordinated by a series of transcriptional and chromatin remodeling events. ATP-dependent chromatin remodeling enzymes, which utilize ATP as an energy source to control chromatin dynamics and regulate the accessibility of chromatin to transcriptional regulators, are critical for oligodendrocyte lineage development and regeneration. In this review, we focus on the latest insights into the spatial and temporal specificity of chromatin remodelers during oligodendrocyte development, myelinogenesis, and regeneration. We will also bring together various plausible mechanisms by which lineage specific transcriptional regulators coordinate with chromatin remodeling factors for programming genomic landscapes to specifically modulate these different processes during developmental myelination and remyelination upon injury.
Topics: Animals; Cell Differentiation; Central Nervous System; Chromatin Assembly and Disassembly; Humans; Myelin Sheath; Oligodendroglia; Remyelination
PubMed: 32460418
DOI: 10.1002/glia.23837