title: LINGO-1 negatively regulates myelination by oligodendrocytes.
abstract: The control of myelination by oligodendrocytes in the CNS is poorly understood. Here we show that LINGO-1 is an important negative regulator of this critical process. LINGO-1 is expressed in oligodendrocytes. Attenuation of its function by dominant-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation and increased myelination competence. Attenuation of LINGO-1 results in downregulation of RhoA activity, which has been implicated in oligodendrocyte differentiation. Conversely, overexpression of LINGO-1 leads to activation of RhoA and inhibition of oligodendrocyte differentiation and myelination. Treatment of oligodendrocyte and neuron cocultures with LINGO-1-Fc resulted in highly developed myelinated axons that have internodes and well-defined nodes of Ranvier. The contribution of LINGO-1 to myelination was verified in vivo through the analysis of LINGO-1 knockout mice. The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGO-1 knockout indicate that LINGO-1 signaling may be critical for CNS myelination.
authors.affiliation: Department of Discovery Biology, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. sha.mi@biogenidec.com
authors.forename: Sha
authors.initials: S
authors.lastname: Mi
authors.forename: Robert H
authors.initials: RH
authors.lastname: Miller
authors.forename: Xinhua
authors.initials: X
authors.lastname: Lee
authors.forename: Martin L
authors.initials: ML
authors.lastname: Scott
authors.forename: Svetlane
authors.initials: S
authors.lastname: Shulag-Morskaya
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Shao
authors.forename: Jufang
authors.initials: J
authors.lastname: Chang
authors.forename: Greg
authors.initials: G
authors.lastname: Thill
authors.forename: Melissa
authors.initials: M
authors.lastname: Levesque
authors.forename: Mingdi
authors.initials: M
authors.lastname: Zhang
authors.forename: Cathy
authors.initials: C
authors.lastname: Hession
authors.forename: Dinah
authors.initials: D
authors.lastname: Sah
authors.forename: Bruce
authors.initials: B
authors.lastname: Trapp
authors.forename: Zhigang
authors.initials: Z
authors.lastname: He
authors.forename: Vincent
authors.initials: V
authors.lastname: Jung
authors.forename: John M
authors.initials: JM
authors.lastname: McCoy
authors.forename: R Blake
authors.initials: RB
authors.lastname: Pepinsky
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D034622:RNA Interference / Q000187:drug effects / Q000502:physiology; D011901:Ranvier's Nodes / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D020318:Rats, Long-Evans; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C482293:LINGO1 protein, human; D008565:Membrane Proteins; D018992:Myelin-Associated Glycoprotein; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C494957:FYN protein, human; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D020742:rhoA GTP-Binding Protein