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      The multiple roles of myelin protein genes during the development of the oligodendrocyte

      research-article
      1 ,   1 , 2
      ASN NEURO
      American Society for Neurochemistry
      amyloid β-peptide (Aβ), calmodulin (CaM), central nervous system (CNS), extracellular matrix (ECM), oligodendrocyte (OL), proteolipid protein (PLP), Aβ, amyloid β-peptide, AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, CaM, calmodulin, CNP, 2′,3′-cyclic nucleotide 3′-phosphodiesterase, CNS, central nervous system, ECM, extracellular matrix, ER, endoplasmic reticulum, GIP, golli-interacting protein, KO, knockout, MAG, myelin-associated glycoprotein, MARCKS, myristoylated alanine-rich C-kinase substrate, MBP, myelin basic protein, MS, multiple sclerosis, OL, oligodendrocyte, OPC, OL precursor cell, PDGF, platelet-derived growth factor, PLP, proteolipid protein, PNS, peripheral nervous system, RNAi, RNA interference, SH3 domain, Src homology 3 domain, SOCC, store-operated Ca2+ channel, VOCC, voltage-operated Ca2+ channel

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          Abstract

          It has become clear that the products of several of the earliest identified myelin protein genes perform functions that extend beyond the myelin sheath. Interestingly, these myelin proteins, which comprise proteolipid protein, 2′,3′-cyclic nucleotide 3′-phosphodiesterase and the classic and golli MBPs (myelin basic proteins), play important roles during different stages of oligodendroglial development. These non-myelin-related functions are varied and include roles in the regulation of process outgrowth, migration, RNA transport, oligodendrocyte survival and ion channel modulation. However, despite the wide variety of cellular functions performed by the different myelin genes, the route by which they achieve these many functions seems to converge upon a common mechanism involving Ca 2+ regulation, cytoskeletal rearrangements and signal transduction. In the present review, the newly emerging functions of these myelin proteins will be described, and these will then be discussed in the context of their contribution to oligodendroglial development.

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          Most cited references136

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          Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination.

          Myelination of axons by oligodendrocytes enables rapid impulse propagation in the central nervous system. But long-term interactions between axons and their myelin sheaths are poorly understood. Here we show that Cnp1, which encodes 2',3'-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly. In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity and physical stability of myelin were not altered in these mice. Genetically, the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in multiple sclerosis lesions, may suffice to cause secondary axonal loss.
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            Myelin basic protein: a multifunctional protein.

            J Boggs (2006)
            Myelin basic protein (MBP), the second most abundant protein in central nervous system myelin, is responsible for adhesion of the cytosolic surfaces of multilayered compact myelin. A member of the 'intrinsically disordered' or conformationally adaptable protein family, it also appears to have several other functions. It can interact with a number of polyanionic proteins including actin, tubulin, Ca(2+)-calmodulin, and clathrin, and negatively charged lipids, and acquires structure on binding to them. It may act as a membrane actin-binding protein, which might allow it to participate in transmission of extracellular signals to the cytoskeleton in oligodendrocytes and tight junctions in myelin. Some size isoforms of MBP are transported into the nucleus and thus they may also bind polynucleotides. Extracellular signals received by myelin or cultured oligodendrocytes cause changes in phosphorylation of MBP, suggesting that MBP is also involved in signaling. Further study of this very abundant protein will reveal how it is utilized by the oligodendrocyte and myelin for different purposes.
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              Vesicular glutamate release from axons in white matter.

              Vesicular release of neurotransmitter is the universal output signal of neurons in the brain. It is generally believed that fast transmitter release is restricted to nerve terminals that contact postsynaptic cells in the gray matter. Here we show in the rat brain that the neurotransmitter glutamate is also released at discrete sites along axons in white matter in the absence of neurons and nerve terminals. The propagation of single action potentials along axons leads to rapid vesicular release of glutamate, which is detected by ionotropic glutamate receptors on local oligodendrocyte precursor cells. Axonal release of glutamate is reliable, involves highly localized calcium microdomain signaling and is strongly calcium cooperative, similar to vesicle fusion at synapses. This axonal transmitter release represents a widespread mechanism for high-fidelity, activity-dependent signaling at the axon-glia interface in white matter.
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                Author and article information

                Journal
                ASN Neuro
                ASN
                ASN NEURO
                American Society for Neurochemistry (9037 Ron Den Lane, Windermere, FL 34786 )
                1759-0914
                17 December 2009
                1 February 2010
                2010
                : 2
                : 1
                : e00027
                Affiliations
                [1]Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095, U.S.A.
                Author notes
                These authors contributed equally to this work.
                2To whom correspondence should be addressed (email acampagnoni@ 123456mednet.ucla.edu ).
                Article
                e00027
                10.1042/AN20090051
                2814326
                20017732
                2c229e9a-1841-4484-9503-3341a2e29592
                © 2010 The Author(s).

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence ( http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commerical use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 November 2009
                : 14 December 2009
                : 17 December 2009
                Categories
                Review Article
                S2
                S5

                Neurosciences
                oligodendrocyte (ol),calmodulin (cam),mag, myelin-associated glycoprotein,central nervous system (cns),ecm, extracellular matrix,rnai, rna interference,ms, multiple sclerosis,vocc, voltage-operated ca2+ channel,marcks, myristoylated alanine-rich c-kinase substrate,aβ, amyloid β-peptide,plp, proteolipid protein,cnp, 2′,3′-cyclic nucleotide 3′-phosphodiesterase,ampa, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid,mbp, myelin basic protein,cns, central nervous system,amyloid β-peptide (aβ),ol, oligodendrocyte,extracellular matrix (ecm),proteolipid protein (plp),pns, peripheral nervous system,pdgf, platelet-derived growth factor,socc, store-operated ca2+ channel,gip, golli-interacting protein,ko, knockout,sh3 domain, src homology 3 domain,cam, calmodulin,opc, ol precursor cell,er, endoplasmic reticulum

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