LINGO-1 negatively regulates myelination by oligodendrocytes.
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.
Mi
Sha
S
Department of Discovery Biology, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. sha.mi@biogenidec.com
Miller
Robert H
RH
Lee
Xinhua
X
Scott
Martin L
ML
Shulag-Morskaya
Svetlane
S
Shao
Zhaohui
Z
Chang
Jufang
J
Thill
Greg
G
Levesque
Melissa
M
Zhang
Mingdi
M
Hession
Cathy
C
Sah
Dinah
D
Trapp
Bruce
B
He
Zhigang
Z
Jung
Vincent
V
McCoy
John M
JM
Pepinsky
R Blake
RB
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
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