Myelination
- 1. Aman Kumar Naik Integrated M.Sc. 9/11/2015 :: National Institute of Science Education and Research :: Myelination
- 2. DOI: 10.1126/science.1190927 , 779 (2010);330Science Ben Emery Regulation of Oligodendrocyte Diffe This copy is for your personal, non-commercia clicking here.colleagues, clients, or customers by , you can orderIf you wish to distribute this article to others here.following the guidelines Permission to republish or repurpose articles or portions o Junewww.sciencemag.org (this infomation is current as of The following resources related to this article are available http://www.sciencemag.org/content/330/6005/779.full.html version of this article at: including high-resolution fUpdated information and services, http://www.sciencemag.org/content/330/6005/779.full.html#rela found at: reA list of selected additional articles on the Science Web sites http://www.sciencemag.org/content/330/6005/779.full.html#ref-l , 20 of which can be accessed freecites 54 articlesThis article subject collections:This article appears in the following DOI: 10.1126/science.1190927 , 779 (2010);330Science Ben Emery Regulation of Oligodendrocyte Differentiation and Myelin This copy is for your personal, non-commercial use only. clicking here.colleagues, clients, or customers by , you can order high-quality copies for yourIf you wish to distribute this article to others here.following the guidelines can be obtained bPermission to republish or repurpose articles or portions of articles ):June 15, 2011www.sciencemag.org (this infomation is current as of The following resources related to this article are available online at http://www.sciencemag.org/content/330/6005/779.full.html version of this article at: including high-resolution figures, can be found in the oUpdated information and services, http://www.sciencemag.org/content/330/6005/779.full.html#related found at: can berelated to this articleA list of selected additional articles on the Science Web sites http://www.sciencemag.org/content/330/6005/779.full.html#ref-list-1 , 20 of which can be accessed free:cites 54 articlesThis article http://www.sciencemag.org/cgi/collection/neuroscience Neuroscience subject collections:This article appears in the following The myelin sheath was not stained in these preparations, thus the existence of a continual cytoplasmic link between oligodendrocytes and myelin was not demonstrated until the advent of electron microscopy. Silver-stained oligodendrocytes (“O”) and a neuroglia/astrocyte (“N”)
- 3. Discovering Myelination Nonmyelinating (Remak-type) Schwann cell engulfs multiple axons of a diameter below 1 μm Schwann cell elaborates myelin ensheathing one axonal segment Oligodendrocytes ensheathing multiple axonal segments Electron-dense intraperiod lines (IPL) Major dense lines (MDL) Schmidt-Lanterman incisures (SLI) provide cytosolic channels Radial components Adhesive tight junction
- 4. Discovering Myelination Schematic depiction as unrolled to visualize structural specializations Antibodies specific for 1. Axonal sodium channel Nav1.6 ( green) 2. Myelin-associated glycoprotein (MAG, orange) Marker for Schmidt-Lanterman incisures 3. Nucleus of the Schwann cell (blue) Illustrating the dimension of the myelin unit Fig. Dissection from the sciatic nerve
- 5. Immature SCs surrounding axon bundles Late embryonic development OR Shortly after birth SCs extend processes into the bundles, selecting and extracting single axons of large diameters (approx. >1 micrometer in the adult mouse) to achieve a SC–axon relationship termed the pro-myelinating stage. Radial axonal sorting * Sox 10, Oct 6, Brn 2, YY1……All Transcrptionfactors Radial axonal sorting Review Molecular mechanisms regulating myelination in the peripheral nervous system Jorge A. Pereira, Fre´de´ric Lebrun-Julien and Ueli Suter Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH Zu¨ rich, CH-8093 Zu¨ rich, Switzerland Glial cells and neurons are engaged in a continuous and highly regulated bidirectional dialog. A remarkable ex- largely due to the relative anatomical simplicity of periph- eral nerves and the consequential experimental opportu- Review Trends in Neurosciences February 2012, Vol. 35, No. 2 Transcriptional control of Myelination in PNS Myelination in PNS
- 6. Epigenetic control of Myelination in PNS Review Review Molecular mechanisms regulating myelination in the peripheral nervous system Jorge A. Pereira, Fre´de´ric Lebrun-Julien and Ueli Suter Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH Zu¨ rich, CH-8093 Zu¨ rich, Switzerland Glial cells and neurons are engaged in a continuous and highly regulated bidirectional dialog. A remarkable ex- ample is the control of myelination. Oligodendrocytes in largely due to the relative anatomical simplicity of periph- eral nerves and the consequential experimental opportu- nities. Although there are significant molecular differences Review Review Trends in Neurosciences February 2012, Vol. 35, No. 2 • Sox10 recruits both HDAC1 and HDAC2 to regulatory regions of the Sox10 and Krox20 loci • In vitro studies showed that miRNA 29a regulates expression of the dosage-sensitive hereditary neuropathy-causing PMP22 • Cell cycle exit help differentiation • MicroRNAs required for minor extent in Radial sorting
- 7. Transcriptional and epigenetic control of PNS myelination Sox10 (SRY-related HMG- box-10) Oct6 (octamer-binding transcription factor-6) Activate Synergistically induce Krox20/Egr2 (early growth response-2) 1. Activate numerous myelin genes 2. Suppress myelination inhibitors 3. Maintain the myelinated state NFATc4 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent-4) Associates with Sox10 to activate 1. Krox20 2. P0 (protein-zero) genes Encodes PNS myelin protein Myelin lamellae compaction and stability Yy1 (Yin yang-1) Regulates Important for Myelination NRG1 type III (NRG1-III) NF-kB (nuclear factor of k light poly- peptide gene enhancer in B cells) Deacetylation Histone deacetylases HDAC1 and HDAC2 Sox10 activate activate
- 8. SREBP cleavage-activating protein (SCAP) Sterol regulatory element-binding proteins (SREBPs) activate deletion Cholesterol and fatty acid synthesis Altered myelin synthesis Severe hypomyelination with uncompacted myelin stretches • Animal Model for PMP22 (peripheral myelin protein-22) based inherited peripheral neuropathies : Reduced expression of genes involved in cholesterol biosynthesis Lpin1 Phosphatidate phosphatase (PAP1) Triacylglycerol biosynthesis deletion Phosphatidic acid MEK–Erk pathway *MEK = Mitogen-activated protein kinase Erk = Extracellular-signal regulated kinase Accumulation activate Demyelination
- 9. Selection of axons and initiation of contact • A minimum calibre is required (~1 µm) • How axons of a minimum calibre are selected for myelination is still not understood Certain cell adhesion molecules L1 NCAM (neural cell adhesion molecule) Polysialylated NCAM Expressed on unmyelinated axons Downregulated during axonal myelination Nerve growth factor (NGF) Activate Tyrosine kinase TrkA receptors Autophosphorylation Cause
- 10. Binding of various adaptor proteins Phospholipase C-γ1 (PLCγ1) Src homology 2 domain-containing transforming protein (SHC) Phosphatidyl-inositol 3–kinase (PI3K) Extracellular signal-regulated kinase 1 (ERK1) Signaling Pathways Converge into Nucleus Cause Transcription of neuronal genes that can modulate the ability of oligodendrocytes and Schwann cells to myelinate
- 11. Axo–glial contact and formation of the node 3 Junctions in a Neuron Paranodal domain Nodal domain Juxtaparanode Axo–glial junction between myelin and the axolemma Caspr (contactin- associated protein/paranodin) contactin, neurofascin 155 (Nfasc155) Nfasc186 (a neuronal isoform of neurofascin) ankyrin G neural–glial-related cell adhesion molecule (NrCAM) βIV-spectrin MECHANISMS OF AXON ENSHEATHMENT AND MYELIN GROWTH Diane L. Sherman and Peter J. Brophy Abstract | The evolution of complex nervous systems in vertebrates has been accompanied by, and probably dependent on, the acquisition of the myelin sheath. Although there has been substantial progress in our understanding of the factors that determine glial cell fate, much less R E V I E W S Centre for Neuroscience Research, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK. Correspondence to P.J.B. e-mail: peter.brophy@ed.ac.uk doi:10.1038/nrn1743 nerve impulse conduction. During vertebrate evolu- tion this has been achieved through the development of myelin-forming glial cells — oligodendrocytes in the CNS, and Schwann cells in the PNS. These cells wrap around axons so that the molecular machinery respon- sible for propagating action potentials is concentrated at regular, discontinuous sites along the axon. These are known as nodes of Ranvier. The presence of myelin as aninternodalinsulatorensuresthatmembranedepolar- ization can only occur at the nodes. The result is rapid, saltatory (from the Latin saltare, to jump, or to dance) nerve conduction. Themyelinsheathisoneofthebeststudiedmamma- lian membranes, not least because of its vital function, and also owing to its abundance and the ease of isola- tion of enriched myelin fractions. Consequently, there is a vast literature on the biochemical and biophysical properties of this membrane in health and disease, and considerable detail has been amassed about the biosynthesis of its constituent lipids and proteins (for a review, see REF. 1). Furthermore, and reflecting our growingunderstandingof hownervoussystems develop cursors have be few years (for re have revealed th number of recep tion factors in the there has been, a our understandi from and which In spite of thi surprisingly little and dynamics o mine how the m around axons in slow in unders nerves to contin These are key q system function myelin as an ins that myelin-form of nodes of Ranv demic interest, a of repair and the NATURE REVIEWS | NEUROSCIENCE he involvement of a steadily increasing ptor signalling pathways and transcrip- edifferentiationofglialcells.Therefore, and continues to be, steady progress in ng of where myelin-forming glia come molecules regulate their specification. s burgeoning knowledge, until recently e was known about the molecular basis f the cell–cell interactions that deter- yelin sheath is extended and stabilized n the first place. Progress has also been tanding the mechanisms that allow nue growing in the postnatal animal. questions for understanding nervous n, as they relate directly to the role of sulator of nerve fibres and to the way ming glia participate in the assembly vier. These issues are of more than aca- s progress in revealing the mechanisms e essential role of myelin-forming glia VOLUME 6 | SEPTEMBER 2005 | 683
- 12. Myelination causes clustering of the sodium channel complex at nodes of Ranvier and axon initial segments MECHANISMS OF AXON ENSHEATHMENT AND MYELIN GROWTH Diane L. Sherman and Peter J. Brophy Abstract | The evolution of complex nervous systems in vertebrates has been accompanied by, and probably dependent on, the acquisition of the myelin sheath. Although there has been substantial progress in our understanding of the factors that determine glial cell fate, much less R E V I E W S Centre for Neuroscience Research, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK. Correspondence to P.J.B. e-mail: peter.brophy@ed.ac.uk doi:10.1038/nrn1743 nerve impulse conduction. During vertebrate evolu- tion this has been achieved through the development of myelin-forming glial cells — oligodendrocytes in the CNS, and Schwann cells in the PNS. These cells wrap around axons so that the molecular machinery respon- sible for propagating action potentials is concentrated at regular, discontinuous sites along the axon. These are known as nodes of Ranvier. The presence of myelin as aninternodalinsulatorensuresthatmembranedepolar- ization can only occur at the nodes. The result is rapid, saltatory (from the Latin saltare, to jump, or to dance) nerve conduction. Themyelinsheathisoneofthebeststudiedmamma- lian membranes, not least because of its vital function, and also owing to its abundance and the ease of isola- tion of enriched myelin fractions. Consequently, there is a vast literature on the biochemical and biophysical properties of this membrane in health and disease, and considerable detail has been amassed about the biosynthesis of its constituent lipids and proteins (for a review, see REF. 1). Furthermore, and reflecting our growingunderstandingof hownervoussystems develop cursors have bee few years (for re have revealed th number of recep tion factors in the there has been, a our understandin from and which In spite of this surprisingly little and dynamics o mine how the m around axons in slow in underst nerves to contin These are key q system function myelin as an ins that myelin-form of nodes of Ranv demic interest, as of repair and the NATURE REVIEWS | NEUROSCIENCE e involvement of a steadily increasing tor signalling pathways and transcrip- edifferentiationofglialcells.Therefore, and continues to be, steady progress in ng of where myelin-forming glia come molecules regulate their specification. s burgeoning knowledge, until recently e was known about the molecular basis f the cell–cell interactions that deter- yelin sheath is extended and stabilized the first place. Progress has also been tanding the mechanisms that allow nue growing in the postnatal animal. uestions for understanding nervous n, as they relate directly to the role of sulator of nerve fibres and to the way ming glia participate in the assembly vier. These issues are of more than aca- s progress in revealing the mechanisms e essential role of myelin-forming glia VOLUME 6 | SEPTEMBER 2005 | 683
- 13. w Review Molecular mechanisms regulating myelination in the peripheral nervous system Jorge A. Pereira, Fre´de´ric Lebrun-Julien and Ueli Suter Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH Zu¨ rich, CH-8093 Zu¨ rich, Switzerland Glial cells and neurons are engaged in a continuous and highly regulated bidirectional dialog. A remarkable ex- ample is the control of myelination. Oligodendrocytes in largely due to the relative anatomical simplicity of periph- eral nerves and the consequential experimental opportu- nities. Although there are significant molecular differences Review Review Trends in Neurosciences February 2012, Vol. 35, No. 2 Schwann Cell – Axon interactions
- 14. Myelin process extension around target axons Contains a high percentage of lipids compared with the plasma membranes Cholesterol is a major constituent High galactolipid content Ceramide Galactosyl Transferase (CGT) Enzyme UDP galactose Encodes CNS PNS Disrupted PARANODAL AXOGLIAL JUNCTIONS Lipids were replaced with glucoanalogs Reduced nerve conduction velocity Normal nerve conduction Myeline Membrane Knock-Out Stops Synthesis of galactolipids
- 15. Cerebroside sulphotransferase Sulphated derivatives CNS PNS Disrupted PARANODAL AXOGLIAL JUNCTIONS Lipids were replaced with glucoanalogs Reduced nerve conduction velocity Normal nerve conduction Knock-Out Stops Synthesis of galactolipids Galactolipid
- 16. Involvement of other cytoskeletal element Schwann cells Oligodendrocytes Rho kinase (ROCK) phosphorylate actin–myosin mechanical transduction regulate myosin light chains Knock-Out Single myelinating process of the Schwann cell splits to form many smaller internodes Sphingosine 1-phosphate receptor 5 (S1P5, also known as EDG8) High-affinity sphingosine 1-phosphate receptor restricted to Oligodendrocytes
- 17. Stimulation of oligodendrocytes with sphingosine 1-phosphate affect two pathway myelin process retraction cell survival mediated through Rho kinase–collapsin response-mediated protein signalling pathway Pertussis toxin-sensitive, Akt (v-akt murine thymoma viral oncogene homologue) dependent pathway mediated through Cdc42-Rac• Fyn extension causeactivate • myelinating Schwann cell–neuron co-cultures cytochalasin D myelination stops disrupt Actin filament
- 18. Demyelination and Remyelination in PNS * Notch, c-Jun……All Transcrptionfactors w Review Molecular mechanisms regulating myelination in the peripheral nervous system Jorge A. Pereira, Fre´de´ric Lebrun-Julien and Ueli Suter Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH Zu¨ rich, CH-8093 Zu¨ rich, Switzerland Glial cells and neurons are engaged in a continuous and highly regulated bidirectional dialog. A remarkable ex- ample is the control of myelination. Oligodendrocytes in largely due to the relative anatomical simplicity of periph- eral nerves and the consequential experimental opportu- nities. Although there are significant molecular differences Review Review Trends in Neurosciences February 2012, Vol. 35, No. 2 • Remyelintion after development which are triggered because of Disease and Injury are not same and different Transcription factor activated during this process.
- 20. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus One of the hippocampal OPCs recorded by Bergles et al. filled with biocytin Antibodies against the OPC marker NG2 OPCs in the CA1 region were patch clamped and their membrane potentials measured in response to L- glutamate stimulation of CA3 neurons *TTX = Tetrodotoxin NATURE |VOL 405 |11 MAY 2000 |www.nature.com .............................................. Glutamatergic synapses o oligodendrocyte precursor cells in the hippocampus Dwight E. Bergles*, J. David B. Roberts², Peter So & Craig E. Jahr* * Vollum Institute, L474, Oregon Health Sciences Unive Oregon 97201, USA ² MRC Anatomical Neuropharmacology Unit, Departm University of Oxford, Oxford OX1 3TH, UK ................................................................................................... Fast excitatory neurotransmission in the cen occurs at specialized synaptic junctions betwe high concentration of glutamate directly channels. Low-af®nity AMPA (a-amino-3-hy xazole propionic acid) and kainate glutamat expressed by some glial cells1 , including oligo sor cells (OPCs). However, the conditions that of glutamate receptors on these non-neuronal Here we report that stimulation of excita hippocampus elicits inward currents in OPC by AMPA receptors. The quantal nature of t their rapid kinetics indicate that they are exocytosis of vesicles ®lled with glutamat these receptors. Some of these AMPA recepto calcium ions, providing a link between axona nal calcium levels in OPCs. Electron microscop that vesicle-®lled axon terminals make synapti NATURE |VOL 405 |11 MAY 2000 |www.nature.com ................................................................. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus Dwight E. Bergles*, J. David B. Roberts², Peter Somogyi² & Craig E. Jahr* * Vollum Institute, L474, Oregon Health Sciences University, Portland, Oregon 97201, USA ² MRC Anatomical Neuropharmacology Unit, Department of Pharmacology, University of Oxford, Oxford OX1 3TH, UK .............................................................................................................................................. Fast excitatory neurotransmission in the central nervous system occurs at specialized synaptic junctions between neurons, where a high concentration of glutamate directly activates receptor channels. Low-af®nity AMPA (a-amino-3-hydroxy-5-methyl iso- xazole propionic acid) and kainate glutamate receptors are also expressed by some glial cells1 , including oligodendrocyte precur- sor cells (OPCs). However, the conditions that result in activation of glutamate receptors on these non-neuronal cells are not known. Here we report that stimulation of excitatory axons in the hippocampus elicits inward currents in OPCs that are mediated by AMPA receptors. The quantal nature of these responses and their rapid kinetics indicate that they are produced by the exocytosis of vesicles ®lled with glutamate directly opposite these receptors. Some of these AMPA receptors are permeable to calcium ions, providing a link between axonal activity and inter- nal calcium levels in OPCs. Electron microscopic analysis revealed that vesicle-®lled axon terminals make synaptic junctions with the 8/8 groups of cells). Paired stimuli p (P2/P1 = 1.7 6 0.1, following the secon facilitation of excit a c Figure 1 Synaptic respons clamp recording of membr 20 pA). b, Evoked respons recorded in voltage-clamp (membrane potential = -9 responses recorded from th biocytin-®lled OPC. d, Mic conjugated streptavidin. e, d. Scale bars for c and d, © 2000 Macmillan Magazines Ltd letters to nature 11. Cesare, P. & McNaughton, P. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin. Proc. Natl Acad. Sci. USA 93, 15435±15439 (1996). 12. Nagy, I. & Rang, H. P. Similarities and differences between the responses of rat sensory neurons to noxious heat and capsaicin. J. Neurosci. 19, 10647±10655 (1999). 13. Nagy, J. I. & Kooy, D. van der. Effects of neonatal capsaicin treatment on nociceptive thresholds in the rat. J. Neurosci. 3, 1145±1150 (1983). 14. Caterina, M. J., Rosen, T. A., Tominaga, M., Brake, A. J. & Julius, D. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398, 436±441 (1999). 15. Hargreaves, K., Dubner, R., Brown, F., Flores, C. & Joris, J. A new and sensitive method for measuring processes of OPCs in both the young and adult hippocampus. These results demonstrate the existence of a rapid signalling path- way from pyramidal neurons to OPCs in the mammalian hippo- campus that is mediated by excitatory, glutamatergic synapses. Oligodendrocytes in the mammalian central nervous system develop from a population of precursor cells during late gestational and early postnatal life2 , providing the insulating sheaths of myelin 11. Cesare, P. & McNaughton, P. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin. Proc. Natl Acad. Sci. USA 93, 15435±15439 (1996). 12. Nagy, I. & Rang, H. P. Similarities and differences between the responses of rat sensory neuron noxious heat and capsaicin. J. Neurosci. 19, 10647±10655 (1999). 13. Nagy, J. I. & Kooy, D. van der. Effects of neonatal capsaicin treatment on nociceptive thresholds i rat. J. Neurosci. 3, 1145±1150 (1983). 14. Caterina, M. J., Rosen, T. A., Tominaga, M., Brake, A. J. & Julius, D. A capsaicin-receptor homol with a high threshold for noxious heat. Nature 398, 436±441 (1999). 15. Hargreaves, K., Dubner, R., Brown, F., Flores, C. & Joris, J. A new and sensitive method for measu thermal nociception in cutaneous hyperalgesia. Pain 32, 77±88 (1988). 16. Kwak, J. Y., Jung, J. Y., Hwang, S. W., Lee, W. T. & Oh, U. A capsaicin-receptor antagonist, capsaze reduces in¯ammation-induced hyperalgesic responses in the rat: evidence for an endogenous capsaicin-like substance. Neuroscience 86, 619±626 (1998). 17. Sasamura, T., Sasaki, M., Tohda, C. & Kuraishi, Y. Existence of capsaicin-sensitive glutamatergi terminals in rat hypothalamus. Neuroreport 9, 2045±2048 (1998). 18. Rogers, D. C. et al. `SHIRPA'Ða comprehensive behavioural and functional analysis of mouse phenotype. Mamm. Genome 8, 711±713 (1997). 19. Yagi, T. et al. A novel selection for homologous recombinants using diptheria toxin A frgament g Anal. Biochem. 214, 77±86 (1993). 20. Torres, R. M. & Kuhn, R. Laboratory Protocols for Conditional Gene Targeting. (Oxford Univ. Pr Oxford, 1997). 21. Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. HPRT-de®cient (Lesch-Nyhan) m embryos derived from germline colonization by cultured cells. Nature 326, 292±295 (1987). 22. Rogers, D. C. et al. Use of SHIRPA and discriminant analysis to characterise marked differences i behavioural phenotype of six inbred mouse strains. Behav. Brain Res. 105, 207±217 (1999). 23. Miliken, G. A. & Johnson, D. E. in Analysis of Messy Data 29±45 (Chapman & Hall, London, 1 Supplementary information is available on Nature's World-Wide Web site (http:// www.nature.com) or as paper copy from the London editorial of®ce of Nature. Acknowledgements The authors would like to acknowledge P. Hayes, J. Nation, S. Pickering and C. David technical assistance, and S. Rastan, F. Walsh, M. Geppert and D. Simmons for valuab critique. Correspondence or requests for materials should be addressed to J.B.D. (e-mail: John_B_Davis@sbphrd.com). ............................................................... Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus Dwight E. Bergles*, J. David B. Roberts², Peter Somogyi² & Craig E. Jahr* * Vollum Institute, L474, Oregon Health Sciences University, Portland, Oregon 97201, USA ² MRC Anatomical Neuropharmacology Unit, Department of Pharmacology University of Oxford, Oxford OX1 3TH, UK
- 21. DOI: 10.1126/science.1190927 , 779 (2010);330Science Ben Emery Regulation of Oligodendrocyte DOI: 10.1126/science.1190927 , 779 (2010);330Science Ben Emery Regulation of Oligodendrocyte Differentiation and PDGF = Inhibit myelination promoting gene and maintain OPC at it’s undifferentiated state Jagged = Expressed on neurons and act as inhibitor for OPC differentiation Id2, Id4, Hes5, Sox6 = Repress myelin gene expression and maintain OPC at it’s undifferentiated state Axonal release of ATP Stimulate Adjacent astrocytes Promyelination cytokine LIF signals Oligodendrocyte differentiation Release miR-219, miR-338 = Target genes that usually act to maintain OPCs in the undifferentiated state, including PDGFRa, Sox6, and Hes5 * still Id2 and Id4 are activated by Tcf4 HDAC
- 22. Two types of growth in Myelination 1. Radial 2. Lateral iversity Hospital, 1211 Geneva, Switzerland y of Go¨ ttingen, 37075 Go¨ ttingen, Germany olecular Physiology of the Brain (CNMPB), 37075 Go¨ ttingen, Germany 4 is a multilayered oligodendrocytes wever, the underly- ing have remained roach of live imag- genetics, we show incorporated adja- most tongue. Sim- s extend laterally, n of a set of closely borated system of e growing myelin king to the leading lose with ongoing ened in adults by idylinositol-(3,4,5)- tes myelin growth. of myelin as a multi- elin outfoldings in y of myelin biogen- s are ensheathed with ble and complex trans- sen and Mirsky, 2005; ., 2008). More than 60 years after the seminal discovery demonstrating that myelin is made by axon-associated glial cells, and not by the axon itself (Ben Geren, 1954), the molecular mechanisms by which the myelin sheath is wrapped around the axon are still largely unknown. This is due in part to the physical limitations of visual- izing membrane dynamics at the nanometer scale and the time span involved (i.e., days in vivo). Even if it represents ‘‘textbook knowledge’’ that oligodendrocytes wrap myelin around an axon by steering a leading process that stays in close contact with the axon, we have almost no experimental data to substantiate this claim. Does the leading edge resemble a glial growth cone-like extension related to the one that drives axonal outgrowth in developing neurons? It has also become apparent that myelin is a dynamically active structure (Young et al., 2013) that can pro- vide metabolic support to associated axons (Fu¨ nfschilling et al., 2012; Lee et al., 2012). However, it remains completely unclear how molecules reach the innermost myelin layer, i.e., passing through a multilamellar stack of membranes. A number of different models have been proposed to explain how a myelin sheath might form in development. According to the ‘‘carpet crawler’’ model (Bunge et al., 1961, 1989), the oligo- dendrocyte forms a process that broadens and extends along the entire axonal segment (the future internode) before it makes one turn and moves underneath the growing sheet. However, at least in the CNS, several morphological features of myelin are incompatible with this model. In particular, it is clear from elec- tron microscopic analysis that the number of myelin layers can vary along the length of a single myelin sheath during its forma- tion (Knobler et al., 1976). Moreover, the molecular forces neces- sary to continuously displace myelin by newly made layers of membrane from underneath might be too high. Some of these shortcomings were reconciled in the ‘‘liquid croissant’’ (Sobottka Cell 156, 277–290, January 16, 2014 ª2014 Elsevier Inc. 277 Myelin Membrane Wr by PI(3,4,5)P3-Depend Growth at the Inner T Nicolas Snaidero,1,2 Wiebke Mo¨ bius,3,12 Tim Czopka,4,5,6, Sandra Goebbels,3 Julia Edgar,3 Doron Merkler,9,10,11 Dav 1Max Planck Institute of Experimental Medicine, Cellular Neuroscie 2Department of Neurology, University of Go¨ ttingen, Robert-Koch-S 3Department of Neurogenetics, Max Planck Institute of Experiment 4Centre for Neuroregeneration 5MS Society Centre for Translational Research 6Euan Mac Donald Centre for Motor Neurone Disease Research University of Edinburgh, Edinburgh EH16 4SB, UK 7MRC Centre for Regenerative Medicine, University of Edinburgh, 8FEI Company, Achtseweg Noord 5, 5651 GG Eindhoven, The Net 9Department of Pathology and Immunology, University of Geneva, 10Division of Clinical Pathology, Geneva University Hospital, 1211 G 11Department of Neuropathology, University of Go¨ ttingen, 37075 G 12Center for Nanoscale Microscopy and Molecular Physiology of th *Correspondence: msimons@gwdg.de http://dx.doi.org/10.1016/j.cell.2013.11.044 Myelin Membrane Wrapping of CNS Axons by PI(3,4,5)P3-Dependent Polarized Growth at the Inner Tongue Nicolas Snaidero,1,2 Wiebke Mo¨ bius,3,12 Tim Czopka,4,5,6,7 Liesbeth H.P. Hekking,8 Cliff Mathisen,8 Dick Verkleij,8 Sandra Goebbels,3 Julia Edgar,3 Doron Merkler,9,10,11 David A. Lyons,4,5,6 Klaus-Armin Nave,3 and Mikael Simons1,2,* 1Max Planck Institute of Experimental Medicine, Cellular Neuroscience, Hermann-Rein-Strasse, 3, 37075 Go¨ ttingen, Germany 2Department of Neurology, University of Go¨ ttingen, Robert-Koch-Strasse, 40, 37075 Go¨ ttingen, Germany 3
- 23. Two types of growth in Myelination cular Physiology of the Brain (CNMPB), 37075 Go¨ ttingen, Germany s a multilayered oligodendrocytes ever, the underly- g have remained ach of live imag- netics, we show corporated adja- st tongue. Sim- extend laterally, of a set of closely orated system of growing myelin ng to the leading se with ongoing ed in adults by ylinositol-(3,4,5)- s myelin growth. myelin as a multi- n outfoldings in of myelin biogen- are ensheathed with and complex trans- n and Mirsky, 2005; 2008). More than 60 years after the seminal discovery demonstrating that myelin is made by axon-associated glial cells, and not by the axon itself (Ben Geren, 1954), the molecular mechanisms by which the myelin sheath is wrapped around the axon are still largely unknown. This is due in part to the physical limitations of visual- izing membrane dynamics at the nanometer scale and the time span involved (i.e., days in vivo). Even if it represents ‘‘textbook knowledge’’ that oligodendrocytes wrap myelin around an axon by steering a leading process that stays in close contact with the axon, we have almost no experimental data to substantiate this claim. Does the leading edge resemble a glial growth cone-like extension related to the one that drives axonal outgrowth in developing neurons? It has also become apparent that myelin is a dynamically active structure (Young et al., 2013) that can pro- vide metabolic support to associated axons (Fu¨ nfschilling et al., 2012; Lee et al., 2012). However, it remains completely unclear how molecules reach the innermost myelin layer, i.e., passing through a multilamellar stack of membranes. A number of different models have been proposed to explain how a myelin sheath might form in development. According to the ‘‘carpet crawler’’ model (Bunge et al., 1961, 1989), the oligo- dendrocyte forms a process that broadens and extends along the entire axonal segment (the future internode) before it makes one turn and moves underneath the growing sheet. However, at least in the CNS, several morphological features of myelin are incompatible with this model. In particular, it is clear from elec- tron microscopic analysis that the number of myelin layers can vary along the length of a single myelin sheath during its forma- tion (Knobler et al., 1976). Moreover, the molecular forces neces- sary to continuously displace myelin by newly made layers of membrane from underneath might be too high. Some of these shortcomings were reconciled in the ‘‘liquid croissant’’ (Sobottka Cell 156, 277–290, January 16, 2014 ª2014 Elsevier Inc. 277 Myelin Membrane Wra by PI(3,4,5)P3-Depende Growth at the Inner To Nicolas Snaidero,1,2 Wiebke Mo¨ bius,3,12 Tim Czopka,4,5,6,7 L Sandra Goebbels,3 Julia Edgar,3 Doron Merkler,9,10,11 David 1Max Planck Institute of Experimental Medicine, Cellular Neuroscienc 2Department of Neurology, University of Go¨ ttingen, Robert-Koch-Stra 3Department of Neurogenetics, Max Planck Institute of Experimental 4Centre for Neuroregeneration 5MS Society Centre for Translational Research 6Euan Mac Donald Centre for Motor Neurone Disease Research University of Edinburgh, Edinburgh EH16 4SB, UK 7MRC Centre for Regenerative Medicine, University of Edinburgh, Ed 8FEI Company, Achtseweg Noord 5, 5651 GG Eindhoven, The Nethe 9Department of Pathology and Immunology, University of Geneva, 12 10Division of Clinical Pathology, Geneva University Hospital, 1211 Ge 11Department of Neuropathology, University of Go¨ ttingen, 37075 Go¨ t 12Center for Nanoscale Microscopy and Molecular Physiology of the *Correspondence: msimons@gwdg.de http://dx.doi.org/10.1016/j.cell.2013.11.044 Myelin Membrane Wrapping of CNS Axons by PI(3,4,5)P3-Dependent Polarized Growth at the Inner Tongue Nicolas Snaidero,1,2 Wiebke Mo¨ bius,3,12 Tim Czopka,4,5,6,7 Liesbeth H.P. Hekking,8 Cliff Mathisen,8 Dick Verkleij,8 Sandra Goebbels,3 Julia Edgar,3 Doron Merkler,9,10,11 David A. Lyons,4,5,6 Klaus-Armin Nave,3 and Mikael Simons1,2,* 1Max Planck Institute of Experimental Medicine, Cellular Neuroscience, Hermann-Rein-Strasse, 3, 37075 Go¨ ttingen, Germany 2Department of Neurology, University of Go¨ ttingen, Robert-Koch-Strasse, 40, 37075 Go¨ ttingen, Germany 3Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse, 3, 37075 Go¨ ttingen, Germany 4Centre for Neuroregeneration
- 24. Synthesis of myelin basic protein (MBP) microRNAs ribosomes MBP mRNA microtubule MECHANISMS OF AXON ENSHEATHMENT AND MYELIN GROWTH Diane L. Sherman and Peter J. Brophy Abstract | The evolution of complex nervous systems in vertebrates has been accompanied by, and probably dependent on, the acquisition of the myelin sheath. Although there has been substantial progress in our understanding of the factors that determine glial cell fate, much less is known about the cellular mechanisms that determine how the myelin sheath is extended and R E V I E W S Centre for Neuroscience Research, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK. Correspondence to P.J.B. e-mail: peter.brophy@ed.ac.uk doi:10.1038/nrn1743 Functional integration of the vertebrate nervous system’s byzantine cytoarchitecture requires rapid nerve impulse conduction. During vertebrate evolu- tion this has been achieved through the development of myelin-forming glial cells — oligodendrocytes in the CNS, and Schwann cells in the PNS. These cells wrap around axons so that the molecular machinery respon- sible for propagating action potentials is concentrated at regular, discontinuous sites along the axon. These are known as nodes of Ranvier. The presence of myelin as aninternodalinsulatorensuresthatmembranedepolar- ization can only occur at the nodes. The result is rapid, saltatory (from the Latin saltare, to jump, or to dance) nerve conduction. Themyelinsheathisoneofthebeststudiedmamma- lian membranes, not least because of its vital function, and also owing to its abundance and the ease of isola- tion of enriched myelin fractions. Consequently, there is a vast literature on the biochemical and biophysical properties of this membrane in health and disease, and considerable detail has been amassed about the biosynthesis of its constituent lipids and proteins (for a review, see REF. 1). Furthermore, and reflecting our growing understanding of how nervous systems develop in general, the embryonic origins and cell lineages of oligodendrocytes and Schwann cells and their pre- cursors have been more clearly defined over the past few years (for reviews, see REFS. 2,3). These discoveries have revealed the involvement of a steadily increasing number of receptor signalling pathways and transcrip- tion factors in the differentiation of glial cells. Therefore, there has been, and continues to be, steady progress in our understanding of where myelin-forming glia come from and which molecules regulate their specification. In spite of this burgeoning knowledge, until recently surprisingly little was known about the molecular basis and dynamics of the cell–cell interactions that deter- mine how the myelin sheath is extended and stabilized around axons in the first place. Progress has also been slow in understanding the mechanisms that allow nerves to continue growing in the postnatal animal. These are key questions for understanding nervous system function, as they relate directly to the role of myelin as an insulator of nerve fibres and to the way that myelin-forming glia participate in the assembly of nodes of Ranvier. These issues are of more than aca- demic interest, as progress in revealing the mechanisms of repair and the essential role of myelin-forming glia is known about the cellular mechanisms that determine how the myelin sheath is extended and stabilized around axons. This review highlights four crucial stages of myelination, namely, the selection of axons and initiation of cell–cell interactions between them and glial cells, the establishment of stable intercellular contact and assembly of the nodes of Ranvier, regulation of myelin thickness and, finally, longitudinal extension of myelin segments in response to the lengthening of axons during postnatal growth. NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | SEPTEMBER 2005 | 683 mbryonic origins and cell lineages of es and Schwann cells and their pre- en more clearly defined over the past views, see REFS. 2,3). These discoveries e involvement of a steadily increasing tor signalling pathways and transcrip- e differentiation of glial cells. Therefore, nd continues to be, steady progress in ng of where myelin-forming glia come molecules regulate their specification. s burgeoning knowledge, until recently e was known about the molecular basis f the cell–cell interactions that deter- yelin sheath is extended and stabilized the first place. Progress has also been tanding the mechanisms that allow nue growing in the postnatal animal. uestions for understanding nervous , as they relate directly to the role of ulator of nerve fibres and to the way ming glia participate in the assembly ier. These issues are of more than aca- s progress in revealing the mechanisms e essential role of myelin-forming glia e nodes of Ranvier, regulation segments in response to the VOLUME 6 | SEPTEMBER 2005 | 683 Basic myelin protein binds to negative surface of plasma membrane
- 25. Radial Axonal Sorting Immune-Electron microscopy of P3-P4 mouse sciatic nerves 4025RESEARCH ARTICLE Development 138, 4025-4037 (2011) doi:10.1242/dev.065490 © 2011. Published by The Company of Biologists Ltd SUMMARY Radial sorting allows the segregation of axons by a single Schwann cell (SC) and is a prerequisite for myelination during Non-redundant function of dystroglycan and 1 integrins in radial sorting of axons Caterina Berti1, *,† , Luca Bartesaghi1, *,‡ , Monica Ghidinelli1 , Desirée Zambroni1 , Gianluca Figlia1,3 , Zu-Lin Chen2 , Angelo Quattrini3 , Lawrence Wrabetz1 and M. Laura Feltri1,§ RESEARCH A Development 138, 4025-4037 (2011) doi:10.1242/dev.065490 © 2011. Published by The Company of Biologists Ltd amultistep Itinvolves onsignals includethe matrixsignals 11)via1 fcongenital- mpairedinthe andismildly ndJenkison, Bycontrast, istaldistricts bothlaminin stricts(Chen asonsforthis derivefrom minins. Deletionofreceptorscontainingthe1integrinsubunitcauses arrestinradialsortingdistally,butonlymilddefectsproximally (Feltrietal.,2002),leavingthelamininreceptorinvolvedinradial sortinginspinalrootsunidentified.Radialsortingdefectsarealso observedinmodelsofotherhumanmusculardystrophies(MDC1D andFukuyama)thataretheresultofmutationsinfukutinor LARGEglycosyltranferases(Levedakouetal.,2005;Saitoetal., 2007),whichhave-dystroglycanassubstrate.Thesedatasuggest eitherthatdystroglycanmediatessortingorthatthese glycosyltransferasesactonotherproteins,suchas1integrins. However,theabsenceofLargeorfukutindoesnotimpair glycosylationof1integrin(Levedakouetal.,2005;Saitoetal., 2007)anddeletionofdystroglycaninSCsdoesnotaffectradial sorting,atleastindistalnerves(Saitoetal.,2003).Thus,the molecularmechanismsbywhichthesemutationsaltersortingare unknown. Finally,themechanismsbywhichdifferentlaminin-receptor pairspromotesortingareincompletelyunderstood.Axonalsorting requiresmultipleevents:theformationof‘families’ofSCswith multipleaxonscontainedinacommonbasallamina(Websteretal., 1973),thematchingofthenumberofaxonsandSCs,theinsertion ofSCprocessesaroundaxonstorecognizeandsegregatelarge ones,andthedefasciculationofsingleaxonswiththeirown daughterSCandbasallamina(MartinandWebster,1973;Webster etal.,1973).Itisunknownwhichlaminin-receptorpairscontribute toeachstep.Forexample,lamininspromotetheformationofSC processesandtheinteractionwithaxons(Yuetal.,2009)via activationofRac1bya1integrinreceptor(Benningeretal., 2007;Nodarietal.,2007),butlamininsalsopromoteSC proliferationandsurvivalviaactivationofPi3K,FakandCdc42 e,20132 llerUniversity, eScientific rkUniversity, non27,1005, DEVELOPMENT4025RESEARCH ARTICLE
- 26. Radial Axonal Sorting 4025RESEARCH ARTICLE Development 138, 4025-4037 (2011) doi:10.1242/dev.065490 © 2011. Published by The Company of Biologists Ltd SUMMARY Non-redundant function of dystroglycan and 1 integrins in radial sorting of axons Caterina Berti1, *,† , Luca Bartesaghi1, *,‡ , Monica Ghidinelli1 , Desirée Zambroni1 , Gianluca Figlia1,3 , Zu-Lin Chen2 , Angelo Quattrini3 , Lawrence Wrabetz1 and M. Laura Feltri1,§ RESEARCH A Development 138, 4025-4037 (2011) doi:10.1242/dev.065490 © 2011. Published by The Company of Biologists Ltd samultistep Itinvolves sonsignals sincludethe matrixsignals 11)via1 . ofcongenital- mpairedinthe andismildly andJenkison, Bycontrast, distaldistricts fbothlaminin istricts(Chen easonsforthis derivefrom aminins. Deletionofreceptorscontainingthe1integrinsubunitcauses arrestinradialsortingdistally,butonlymilddefectsproximally (Feltrietal.,2002),leavingthelamininreceptorinvolvedinradial sortinginspinalrootsunidentified.Radialsortingdefectsarealso observedinmodelsofotherhumanmusculardystrophies(MDC1D andFukuyama)thataretheresultofmutationsinfukutinor LARGEglycosyltranferases(Levedakouetal.,2005;Saitoetal., 2007),whichhave-dystroglycanassubstrate.Thesedatasuggest eitherthatdystroglycanmediatessortingorthatthese glycosyltransferasesactonotherproteins,suchas1integrins. However,theabsenceofLargeorfukutindoesnotimpair glycosylationof1integrin(Levedakouetal.,2005;Saitoetal., 2007)anddeletionofdystroglycaninSCsdoesnotaffectradial sorting,atleastindistalnerves(Saitoetal.,2003).Thus,the molecularmechanismsbywhichthesemutationsaltersortingare unknown. Finally,themechanismsbywhichdifferentlaminin-receptor pairspromotesortingareincompletelyunderstood.Axonalsorting requiresmultipleevents:theformationof‘families’ofSCswith multipleaxonscontainedinacommonbasallamina(Websteretal., 1973),thematchingofthenumberofaxonsandSCs,theinsertion ofSCprocessesaroundaxonstorecognizeandsegregatelarge ones,andthedefasciculationofsingleaxonswiththeirown daughterSCandbasallamina(MartinandWebster,1973;Webster etal.,1973).Itisunknownwhichlaminin-receptorpairscontribute toeachstep.Forexample,lamininspromotetheformationofSC processesandtheinteractionwithaxons(Yuetal.,2009)via activationofRac1bya1integrinreceptor(Benningeretal., 2007;Nodarietal.,2007),butlamininsalsopromoteSC proliferationandsurvivalviaactivationofPi3K,FakandCdc42 ute,20132 fellerUniversity, eleScientific orkUniversity, ugnon27,1005, DEVELOPMENT4025RESEARCH ARTICLE
- 27. • Understanding Biomechanical Pathway which triggers genes • Understanding MBP mRNA transport • Understanding Remyelination • Treatment of disease such as Leukodystrophies, Neuropathy, Multiple sclerosis • OPC response to Neuron excitation : Myelin Plasticity *Myelination in the human brain can be triggered by functional activity, including reading, practicing the piano, and juggling . (Bengtsson et al. 2005, Keller & Just et al. 2009, Liu et al. 2012, Scholz et al. 2009) *In adult rodents, the training of even simple motor tasks stimulates myelination dependent on the region. (Sampaio-Baptista et al. 2013) *Social isolation negatively impacts myelination in both pubescent and adult mice. (Makinodan et al. 2012) (Liu et al. 2012) Future Advancement
- 28. Thank You Oops!! I am naked Yeah!! Now I am clothed Thanks to oligo and Schwanny