-
Current Opinion in Neurobiology Dec 2023Oligodendrocytes are best known for wrapping myelin, a unique specialization that enables energy-efficient and fast axonal impulse propagation in white matter tracts and... (Review)
Review
Oligodendrocytes are best known for wrapping myelin, a unique specialization that enables energy-efficient and fast axonal impulse propagation in white matter tracts and fibers of the cortical circuitry. However, myelinating oligodendrocytes have additional metabolic functions that are only gradually understood, including the regulated release of pyruvate/lactate and extracellular vesicles, both of which are in support of the axonal energy balance. The axon-supportive functions of glial cells are older than myelin in nervous system evolution and implicate oligodendrocyte dysfunction and loss of myelin integrity as a risk factor for progressive neurodegeneration in brain diseases.
Topics: Myelin Sheath; Oligodendroglia; Brain; Axons; Energy Metabolism
PubMed: 37703600
DOI: 10.1016/j.conb.2023.102782 -
ASN Neuro 2023Myelination contributes not only to the rapid nerve conduction but also to axonal insulation and protection. In the central nervous system (CNS), the initial myelination... (Review)
Review
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.
Topics: Central Nervous System; Myelin Sheath; Axons; Oligodendroglia; Signal Transduction
PubMed: 36974372
DOI: 10.1177/17590914231163039 -
Glia Mar 2022Oligodendrocytes are the cells that myelinate axons and provide trophic support to neurons in the CNS. Their dysfunction has been associated with a group of disorders... (Review)
Review
Oligodendrocytes are the cells that myelinate axons and provide trophic support to neurons in the CNS. Their dysfunction has been associated with a group of disorders known as demyelinating diseases, such as multiple sclerosis. Oligodendrocytes are derived from oligodendrocyte precursor cells, which differentiate into premyelinating oligodendrocytes and eventually mature oligodendrocytes. The development and function of oligodendrocytes are tightly regulated by a variety of molecules, including laminin, a major protein of the extracellular matrix. Accumulating evidence suggests that laminin actively regulates every aspect of oligodendrocyte biology, including survival, migration, proliferation, differentiation, and myelination. How can laminin exert such diverse functions in oligodendrocytes? It is speculated that the distinct laminin isoforms, laminin receptors, and/or key signaling molecules expressed in oligodendrocytes at different developmental stages are the reasons. Understanding molecular targets and signaling pathways unique to each aspect of oligodendrocyte biology will enable more accurate manipulation of oligodendrocyte development and function, which may have implications in the therapies of demyelinating diseases. Here in this review, we first introduce oligodendrocyte biology, followed by the expression of laminin and laminin receptors in oligodendrocytes and other CNS cells. Next, the functions of laminin in oligodendrocyte biology, including survival, migration, proliferation, differentiation, and myelination, are discussed in detail. Last, key questions and challenges in the field are discussed. By providing a comprehensive review on laminin's roles in OL lineage cells, we hope to stimulate novel hypotheses and encourage new research in the field.
Topics: Cell Differentiation; Laminin; Myelin Sheath; Neurogenesis; Oligodendrocyte Precursor Cells; Oligodendroglia
PubMed: 34773273
DOI: 10.1002/glia.24117 -
Acta Neuropathologica Jan 2010Oligodendrocytes are the myelinating cells of the central nervous system (CNS). They are the end product of a cell lineage which has to undergo a complex and precisely... (Review)
Review
Oligodendrocytes are the myelinating cells of the central nervous system (CNS). They are the end product of a cell lineage which has to undergo a complex and precisely timed program of proliferation, migration, differentiation, and myelination to finally produce the insulating sheath of axons. Due to this complex differentiation program, and due to their unique metabolism/physiology, oligodendrocytes count among the most vulnerable cells of the CNS. In this review, we first describe the different steps eventually culminating in the formation of mature oligodendrocytes and myelin sheaths, as they were revealed by studies in rodents. We will then show differences and similarities of human oligodendrocyte development. Finally, we will lay out the different pathways leading to oligodendrocyte and myelin loss in human CNS diseases, and we will reveal the different principles leading to the restoration of myelin sheaths or to a failure to do so.
Topics: Animals; Cell Death; Central Nervous System; Central Nervous System Diseases; Humans; Myelin Sheath; Nerve Fibers, Myelinated; Oligodendroglia; Species Specificity
PubMed: 19847447
DOI: 10.1007/s00401-009-0601-5 -
Cells Nov 2022Myelin, critical for the correct function of the nervous system, is organized in different patterns that can include long non-myelinated axonal segments. How myelin...
Myelin, critical for the correct function of the nervous system, is organized in different patterns that can include long non-myelinated axonal segments. How myelin patterning is regulated remains unexplained. The carbohydrate-binding protein galectin-4 (Gal-4) influences oligodendrocyte differentiation in vitro and is associated with non-myelinable axon segments (NMS) in cultured neurons. In consequence, Gal-4 has been proposed as a myelin patterning regulator, although no in vivo studies have corroborated this hypothesis. We used Gal-4-deficient mice (Lgals4-KO) to study the role of Gal-4 in cortical myelination in vivo. We show that cultured neurons of Lgals4-KO mice form NMS that are regulated as in control neurons. In addition, oligodendrocyte/myelin markers expression measured by biochemical and immunochemical means, and cortical myelin microstructure studied by in-depth image analysis appear unaltered in these animals. Consistently, myelin displays an essentially normal function assessed by in vivo electrophysiology and locomotion analyses. In conclusion, cortical myelin of Lgals4-KO mice does not show any significant defect in composition, organization or function, pointing to a negligible role of Gal-4 in myelination in vivo or, as discussed, to unknown mechanisms that compensate its absence.
Topics: Animals; Mice; Galectin 4; Oligodendroglia; Myelin Sheath; Axons; Neurogenesis
PubMed: 36359880
DOI: 10.3390/cells11213485 -
Brain Research Jun 2016Myelinated axons with nodes of Ranvier are an evolutionary elaboration common to essentially all jawed vertebrates. Myelin made by Schwann cells in our peripheral... (Review)
Review
Myelinated axons with nodes of Ranvier are an evolutionary elaboration common to essentially all jawed vertebrates. Myelin made by Schwann cells in our peripheral nervous system and oligodendrocytes in our central nervous system has been long known to facilitate rapid energy efficient nerve impulse propagation. However, it is now also clear, particularly in the central nervous system, that myelin is not a simple static insulator but that it is dynamically regulated throughout development and life. New myelin sheaths can be made by newly differentiating oligodendrocytes, and mature myelin sheaths can be stimulated to grow again in the adult. Furthermore, numerous studies in models from fish to man indicate that neuronal activity can affect distinct stages of oligodendrocyte development and the process of myelination itself. This begs questions as to how these effects of activity are mediated at a cellular and molecular level and whether activity-driven adaptive myelination is a feature common to all myelinated axons, or indeed all oligodendrocytes, or is specific to cells or circuits with particular functions. Here we review the recent literature on this topic, elaborate on the key outstanding questions in the field, and look forward to future studies that incorporate investigations in systems from fish to man that will provide further insight into this fundamental aspect of nervous system plasticity. This article is part of a Special Issue entitled SI: Myelin Evolution.
Topics: Animals; Biological Evolution; Humans; Learning; Myelin Sheath; Neuronal Plasticity; Neurons
PubMed: 26498877
DOI: 10.1016/j.brainres.2015.10.026 -
Developmental Cell Feb 2015Vertebrate myelination is an evolutionary advancement essential for motor, sensory, and higher-order cognitive function. CNS myelin, a multilamellar differentiation of... (Review)
Review
Vertebrate myelination is an evolutionary advancement essential for motor, sensory, and higher-order cognitive function. CNS myelin, a multilamellar differentiation of the oligodendrocyte plasma membrane, ensheaths axons to facilitate electrical conduction. Myelination is one of the most pivotal cell-cell interactions for normal brain development, involving extensive information exchange between differentiating oligodendrocytes and axons. The molecular mechanisms of myelination are discussed, along with new perspectives on oligodendrocyte plasticity and myelin remodeling of the developing and adult CNS.
Topics: Animals; Axons; Brain; Cell Differentiation; Humans; Myelin Sheath; Neurons; Oligodendroglia
PubMed: 25710531
DOI: 10.1016/j.devcel.2015.01.016 -
Methods in Cell Biology 2017Myelin is a lipid-rich sheath formed by the spiral wrapping of specialized glial cells around axon segments. Myelinating glia allow for rapid transmission of nerve... (Review)
Review
Myelin is a lipid-rich sheath formed by the spiral wrapping of specialized glial cells around axon segments. Myelinating glia allow for rapid transmission of nerve impulses and metabolic support of axons, and the absence of or disruption to myelin results in debilitating motor, cognitive, and emotional deficits in humans. Because myelin is a jawed vertebrate innovation, zebrafish are one of the simplest vertebrate model systems to study the genetics and development of myelinating glia. The morphogenetic cellular movements and genetic program that drive myelination are conserved between zebrafish and mammals, and myelin develops rapidly in zebrafish larvae, within 3-5days postfertilization. Myelin ultrastructure can be visualized in the zebrafish from larval to adult stages via transmission electron microscopy, and the dynamic development of myelinating glial cells may be observed in vivo via transgenic reporter lines in zebrafish larvae. Zebrafish are amenable to genetic and pharmacological screens, and screens for myelinating glial phenotypes have revealed both genes and drugs that promote myelin development, many of which are conserved in mammalian glia. Recently, zebrafish have been employed as a model to understand the complex dynamics of myelinating glia during development and regeneration. In this chapter, we describe these key methodologies and recent insights into mechanisms that regulate myelination using the zebrafish model.
Topics: Animals; Animals, Genetically Modified; Axons; Humans; Larva; Molecular Biology; Myelin Sheath; Neuroglia; Zebrafish
PubMed: 28129853
DOI: 10.1016/bs.mcb.2016.08.001 -
Progress in Neurobiology Aug 2023Myelin improves axonal conduction velocity and is essential for nerve development and regeneration. In peripheral nerves, Schwann cells depend on bidirectional...
Myelin improves axonal conduction velocity and is essential for nerve development and regeneration. In peripheral nerves, Schwann cells depend on bidirectional mechanical and biochemical signaling to form the myelin sheath but the mechanism underlying this process is not understood. Rho GTPases are integrators of "outside-in" signaling that link cytoskeletal dynamics with cellular architecture to regulate morphology and adhesion. Using Schwann cell-specific gene inactivation in the mouse, we discovered that RhoA promotes the initiation of myelination, and is required to both drive and terminate myelin growth at different stages of peripheral myelination, suggesting developmentally-specific modes of action. In Schwann cells, RhoA targets actin filament turnover, via Cofilin 1, actomyosin contractility and cortical actin-membrane attachments. This mechanism couples actin cortex mechanics with the molecular organization of the cell boundary to target specific signaling networks that regulate axon-Schwann cell interaction/adhesion and myelin growth. This work shows that RhoA is a key component of a biomechanical response required to control Schwann cell state transitions for proper myelination of peripheral nerves.
Topics: Mice; Animals; Actins; Schwann Cells; Myelin Sheath; Peripheral Nerves; Axons
PubMed: 37315917
DOI: 10.1016/j.pneurobio.2023.102481 -
ASN Neuro 2022Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and neurodegeneration. Life expectancy and age of... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and neurodegeneration. Life expectancy and age of onset in MS patients have been rising over the last decades, and previous studies have shown that age affects disease progression. Therefore, age appears as one of the most important factors in accumulating disability in MS patients. Indeed, the degeneration of oligodendrocytes (OGDs) and OGD precursors (OPCs) increases with age, in association with increased inflammatory activity of astrocytes and microglia. Similarly, age-related neuronal changes such as mitochondrial alterations, an increase in oxidative stress, and disrupted paranodal junctions can impact myelin integrity. Conversely, once myelination is complete, the long-term integrity of axons depends on OGD supply of energy. These alterations determine pathological myelin changes consisting of myelin outfolding, splitting, and accumulation of multilamellar fragments. Overall, these data demonstrate that old mature OGDs lose their ability to produce and maintain healthy myelin over time, to induce myelination, and to remodel pre-existing myelinated axons that contribute to neural plasticity in the CNS. Furthermore, as observed in other tissues, aging induces a general decline in regenerative processes and, not surprisingly, progressively hinders remyelination in MS. In this context, this review will provide an overview of the current knowledge of age-related changes occurring in cells of the oligodendroglial lineage and how they impact myelin synthesis, axonal degeneration, and remyelination efficiency.
Topics: Axons; Humans; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Remyelination
PubMed: 35938615
DOI: 10.1177/17590914221118502