oligodendrocyte myelin structure
4904615
Oligodendrocyte Nf1 Controls Aberrant Notch Activation and Regulates Myelin Structure and Behavior
SUMMARY The RASopathy neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. In NF1 patients, neurological issues may result from damaged myelin, and mice with a neurofibromin gene (Nf1) mutation show white matter (WM) defects including myelin decompaction. Using mouse genetics, we find that altered Nf1 gene dose in mature oligodendrocytes results in progressive myelin defects and behavioral abnormalities mediated by aberrant Notch activation. Blocking Notch, upstream mitogen activated protein kinase (MAPK) or nitric oxide signaling rescues myelin defects in hemizygous Nf1 mutants, and pharmacological gamma secretase inhibition rescues aberrant behavior with no effects in wild type (WT) mice. Concomitant pathway inhibition rescues myelin abnormalities in homozygous mutants. Notch activation is also observed in Nf1+ mouse brains, and cells containing active Notch are increased in NF1 patient WM. We thus identify Notch as an Nf1 effector regulating myelin structure and behavior in a RASopathy and suggest that inhibition of Notch signaling may be a therapeutic strategy for NF1.
Cell reports
Alejandro Lopez-Juarez Haley E Titus Sadiq H Silbak Joshua W Pressler Tilat A Rizvi Madeleine Bogard Michael R Bennett Georgianne M Ciraolo MichaelT Williams Charles V Vorhees Nancy Ratner
46797229
Oligodendrocyte RasG12V expressed in its endogenous locus disrupts myelin structure through increased MAPK, nitric oxide, and notch signaling
Costello syndrome (CS) is a gain of function Rasopathy caused by heterozygous activating mutations in the HRAS gene. Patients show brain dysfunction that can include abnormal brain white matter. Transgenic activation of HRas in the entire mouse oligodendrocyte lineage resulted in myelin defects and behavioral abnormalities, suggesting roles for disrupted myelin in CS brain dysfunction. Here, we studied a mouse model in which the endogenous HRas gene is conditionally replaced by mutant HRasG12V in mature oligodendrocytes, to separate effects in mature myelinating cells from developmental events. Increased myelin thickness due to decompaction was detectable within one month of HRasG12V expression in the corpus callosum of adult mice. Increases in active ERK and Nitric Oxide (NO) were present in HRas mutants and inhibition of NO synthase (NOS) or MEK each partially rescued myelin decompaction. In addition, genetic or pharmacologic inhibition of Notch signaling improved myelin compaction. Complete rescue of myelin structure required dual drug treatments combining MAPK, NO, or Notch inhibition; with MEK NOS blockade producing the most robust effect. We suggest that individual or concomitant blockade of these pathways in CS patients may improve aspects of brain function.
Glia
Haley E Titus Alejandro Lopez-Juarez Sadiq H Silbak Tilat A Rizvi Madeleine Bogard Nancy Ratner
211087384
Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair
Myelin is an essential structure that protects axons, provides metabolic support to neurons and allows fast nerve transmission. Several neurological diseases, such as multiple sclerosis, are characterized by myelin damage, which is responsible of severe functional impairment. Myelin repair requires the timely recruitment of adult oligodendrocyte precursor cells (OPCs) at the lesion sites, their differentiation and maturation into myelinating oligodendrocytes. As a consequence, OPCs undergo profound changes in their morphology, functions, and interactions with other cells and extracellular environment, thus requiring the reorganization of both their lipid metabolism and their membrane composition, which is substantially different compared to other plasma membranes. Despite the growing knowledge in oligodendroglia biology and in the mechanisms involved in OPC mediated regeneration, the identification of strategies to promote remyelination still remains a challenge. Here, we describe how altered lipid metabolism in oligodendrocytes influences the pathogenesis of demyelination, and we show that several FDA approved drugs with a previously unknown remyelination potential do act on cholesterol and lipid biosynthetic pathways. Since the interplay between myelin lipids and axons is strictly coordinated by the extracellular matrix (ECM) we also discuss the role of different ECM components, and report the last findings on new ECM modifiers able to foster endogenous remyelination.
Journal of clinical medicine
Davide Marangon Marta Boccazzi Davide Lecca Marta Fumagalli
221620535
Lipids in regulating oligodendrocyte structure and function.
Oligodendrocytes enwrap central nervous system axons with myelin, a lipid enriched highly organized multi layer membrane structure that allows for fast long distance saltatory conduction of neuronal impulses. Myelin has an extremely high lipid content ~80 of its dry weight) and a peculiar lipid composition, with a 2:2:1 cholesterol:phospholipid:glycolipid ratio. Inherited neurodegenerative diseases of the lipids (caused by mutations in lipogenic enzymes) often present oligodendrocyte and/or myelin defects which contribute to the overall disease pathophysiology. These phenomena triggered an increasing number of studies over the functions lipid exert to shape and maintain myelin, and brought to the finding that lipids are more than only structural building blocks. They act as signaling molecules to drive proliferation and differentiation of oligodendrocyte progenitor cells, as well as proliferation of premyelinating oligodendrocytes, and their maturation into myelinating ones. Here, we summarize key findings in these areas, while presenting the main related human diseases. Despite many advances in the field, various questions remain open which we briefly discuss. This article is part of a special issue entitled "Role of Lipids in CNS Cell Physiology and Pathology"
Seminars in cell developmental biology
Laura Montani
1057447
Oligodendrocyte Myelin Glycoprotein Does Not Influence Node of Ranvier Structure or Assembly
Oligodendrocyte myelin glycoprotein (OMgp) is expressed by both neurons and oligodendrocytes in the CNS. It has been implicated in growth cone collapse and neurite outgrowth inhibition by signaling through the Nogo receptor and paired Ig like receptor B (PirB) OMgp was also reported to be an extracellular matrix (ECM) protein surrounding CNS nodes of Ranvier and proposed to function as (1) an inhibitor of nodal collateral sprouting and (2) an important contributor to proper nodal and paranodal architecture. However, we show here that the anti OMgp antiserum used in previous studies to define the functions of OMgp at nodes is not specific. Among all reported nodal ECM components, the antiserum exhibited strong cross reactivity against versican V2 isoform, a chondroitin sulfate proteoglycan. Furthermore, the OMgp antiserum labeled OMgp null nodes, but not nodes from versican V2 deficient mice, and preadsorption of the OMgp antiserum with recombinant versican V2 blocked nodal labeling. Analysis of CNS nodes in OMgp null mice failed to reveal any nodal or paranodal defects, or increased nodal collateral sprouting, indicating that OMgp does not participate in CNS node of Ranvier assembly or maintenance. We successfully identified a highly specific anti OMgp antibody and observed OMgp staining in white matter only after initiation of myelination. OMgp immunoreactivity decorated the surface of mature myelinated axons, but was excluded from compact myelin and nodes. Together, our results strongly argue against the nodal localization of OMgp and its proposed functions at nodes, and reveal OMgp's authentic localization relative to nodes and myelin.
The Journal of Neuroscience
Kae-Jiun Chang Keiichiro Susuki Maria T Dours-Zimmermann Dieter R Zimmermann Matthew N Rasband
30528915
A combined NMR and molecular dynamics simulation study to determine the conformational properties of rat/mouse 35 55 myelin oligodendrocyte glycoprotein epitope implicated in the induction of experimental autoimmune encephalomyelitis
A combined NMR and molecular dynamics simulation study to determine the conformational properties of rat/mouse 35 55 myelin oligodendrocyte glycoprotein epitope implicated in the induction of experimental autoimmune encephalomyelitis Dimitrios Ntountaniotis, Marianna Vanioti, Golfo G. Kordopati, Tahsin F. Kellici Konstantinos D. Marousis, Thomas Mavromoustakos* Georgios A. Spyroulias, Simona Golic Grdadolnik and Theodore V. Tselios* Department of Chemistry, National and Kapodistrian University of Athens, Zografou 15771, Athens, Greece; Department of Chemistry, University of Patras, Patras 26504, Greece; Department of Chemistry, University of Ioannina, Ioannina 45110, Greece; Department of Pharmacy, University of Patras, Patras 26504, Greece; Department of Biomolecular Structure, National Institute of Chemistry, Hajdrihova 19, SI 1001 Ljubljana, Slovenia
Journal of biomolecular structure dynamics
Dimitrios Ntountaniotis Marianna Vanioti Golfo G Kordopati Tahsin F Kellici Konstantinos D Marousis Thomas M Mavromoustakos Georgios A Spyroulias Simona Golic Grdadolnik Theodore V Tselios
2997358
CXXC5 plays a role as a transcription activator for myelin genes on oligodendrocyte differentiation
Myelination in corpus callosum plays important role for normal brain functions by transferring neurological information between various brain regions. However, the factors controlling expression of myelin genes in myelination are poorly understood. Here, CXXC5, a recently identified protein with CXXC type zinc finger DNA binding motif, was characterized as a transcriptional activator of major myelin genes. We identified expression of CXXC5 expression was increased by Wnt/b catenin signaling. CXXC5 specifically expressed in the white matter induced expression of myelin genes through the direct binding of CXXC DNA binding motif of CXXC5 on the MBP promoter. During the differentiation of neural stem cells (NSCs) of CXXC5 mice, the expressions of myelin genes were simultaneously reduced. The CXXC5 mice exhibited severely reduction of myelin genes expression in corpus callosum as well as abnormalities in myelin structure. The disrupted structural integrity of myelin in the CXXC5 mice resulted in reduced electrical conduction amplitudes at corpus callosum. These findings indicate that the regulation of myelin genes expression by CXXC5 is important for forming myelin structure involved with axonal electrical signal transfer in the corpus callosum. GLIA 2016;64:350 362
Glia
Mi-Yeon Kim Hyun-Yi Kim Jiso Hong Daesoo Kim Hyojung Lee Eunji Cheong Yangsin Lee Jurgen Roth Dong Goo Kim Do Sik Min Kang-Yell Choi
12653229
Erratum to: Anosmin 1 over expression regulates oligodendrocyte precursor cell proliferation, migration and myelin sheath thickness
During development of the central nervous system, anosmin 1 (A1) works as a chemotropic cue contributing to axonal outgrowth and collateralization, as well as modulating the migration of different cell types, fibroblast growth factor receptor 1 (FGFR1) being the main receptor involved in all these events. To further understand the role of A1 during development, we have analysed the over expression of human A1 in a transgenic mouse line. Compared with control mice during development and in early adulthood, A1 over expressing transgenic mice showed an enhanced oligodendrocyte precursor cell (OPC) proliferation and a higher number of OPCs in the subventricular zone and in the corpus callosum (CC) The migratory capacity of OPCs from the transgenic mice is increased in vitro due to a higher basal activation of ERK1/2 mediated through FGFR1 and they also produced more myelin basic protein (MBP) In vivo, the over expression of A1 resulted in an elevated number of mature oligodendrocytes with higher levels of MBP mRNA and protein, as well as increased levels of activation of the ERK1/2 proteins, while electron microscopy revealed thicker myelin sheaths around the axons of the CC in adulthood. Also in the mature CC, the nodes of Ranvier were significantly longer and the conduction velocity of the nerve impulse in vivo was significantly increased in the CC of A1 over expressing transgenic mice. Altogether, these data confirmed the involvement of A1 in oligodendrogliogenesis and its relevance for myelination.
Brain Structure and Function
Veronica Murcia-Belmonte P F Esteban Jose Martinez-Hernandez Agnes Gruart Rafael Lujan Jose Maria Delgado-Garcia Fernando de Castro
5153835
Movement and structure of mitochondria in oligodendrocytes and their myelin sheaths
Mitochondria play several crucial roles in the life of oligodendrocytes. During development of the myelin sheath they are essential providers of carbon skeletons and energy for lipid synthesis. During normal brain function their consumption of pyruvate will be a key determinant of how much lactate is available for oligodendrocytes to export to power axonal function. Finally, during calcium overload induced pathology, as occurs in ischemia, mitochondria may buffer calcium or induce apoptosis. Despite their important functions, very little is known of the properties of oligodendrocyte mitochondria, and mitochondria have never been observed in the myelin sheaths. We have now used targeted expression of fluorescent mitochondrial markers to characterize the location and movement of mitochondria within oligodendrocytes. We show for the first time that mitochondria are able to enter and move within the myelin sheath. Within the myelin sheath the highest number of mitochondria was in the cytoplasmic ridges along the sheath. Mitochondria moved more slowly than in neurons and, in contrast to their behavior in neurons and astrocytes, their movement was increased rather than inhibited by glutamate activating NMDA receptors. By electron microscopy we show that myelin sheath mitochondria have a low surface area of cristae, which suggests a low ATP production. These data specify fundamental properties of the oxidative phosphorylation system in oligodendrocytes, the glial cells that enhance cognition by speeding action potential propagation and provide metabolic support to axons. GLIA 2016;64:810 825
Glia
Johanne Egge Rinholm Koen Vervaeke Michael R Tadross Ariana N Tkachuk Benjamin G Kopek Timothy A Brown Linda H Bergersen David A Clayton
52810493
Anosmin 1 over expression regulates oligodendrocyte precursor cell proliferation, migration and myelin sheath thickness
During development of the central nervous system, anosmin 1 (A1) works as a chemotropic cue contributing to axonal outgrowth and collateralization, as well as modulating the migration of different cell types, fibroblast growth factor receptor 1 (FGFR1) being the main receptor involved in all these events. To further understand the role of A1 during development, we have analysed the over expression of human A1 in a transgenic mouse line. Compared with control mice during development and in early adulthood, A1 over expressing transgenic mice showed an enhanced oligodendrocyte precursor cell (OPC) proliferation and a higher number of OPCs in the subventricular zone and in the corpus callosum (CC) The migratory capacity of OPCs from the transgenic mice is increased in vitro due to a higher basal activation of ERK1/2 mediated through FGFR1 and they also produced more myelin basic protein (MBP) In vivo, the over expression of A1 resulted in an elevated number of mature oligodendrocytes with higher levels of MBP mRNA and protein, as well as increased levels of activation of the ERK1/2 proteins, while electron microscopy revealed thicker myelin sheaths around the axons of the CC in adulthood. Also in the mature CC, the nodes of Ranvier were significantly longer and the conduction velocity of the nerve impulse in vivo was significantly increased in the CC of A1 over expressing transgenic mice. Altogether, these data confirmed the involvement of A1 in oligodendrogliogenesis and its relevance for myelination.
Brain Structure and Function
Veronica Murcia-Belmonte P F Esteban Jose Martinez-Hernandez Agnes Gruart Rafael Lujan Jose Maria Delgado-Garcia Fernando de Castro