title: LINGO-1, a transmembrane signaling protein, inhibits oligodendrocyte differentiation and myelination through intercellular self-interactions.
abstract: Overcoming remyelination failure is a major goal of new therapies for demyelinating diseases like multiple sclerosis. LINGO-1, a key negative regulator of myelination, is a transmembrane signaling protein expressed in both neurons and oligodendrocytes. In neurons, LINGO-1 is an integral component of the Nogo receptor complex, which inhibits axonal growth via RhoA. Because the only ligand-binding subunit of this complex, the Nogo receptor, is absent in oligodendrocytes, the extracellular signals that inhibit myelination through a LINGO-1-mediated mechanism are unknown. Here we show that LINGO-1 inhibits oligodendrocyte terminal differentiation through intercellular interactions and is capable of a self-association in trans. Consistent with previous reports, overexpression of full-length LINGO-1 inhibited differentiation of oligodendrocyte precursor cells (OPCs). Unexpectedly, treatment with a soluble recombinant LINGO-1 ectodomain also had an inhibitory effect on OPCs and decreased myelinated axonal segments in cocultures with neurons from dorsal root ganglia. We demonstrated LINGO-1-mediated inhibition of OPCs through intercellular signaling by using a surface-bound LINGO-1 construct expressed ectopically in astrocytes. Further investigation showed that the soluble LINGO-1 ectodomain can interact with itself in trans by binding to CHO cells expressing full-length LINGO-1. Finally, we observed that soluble LINGO-1 could activate RhoA in OPCs. We propose that LINGO-1 acts as both a ligand and a receptor and that the mechanism by which it negatively regulates OPC differentiation and myelination is mediated by a homophilic intercellular interaction. Disruption of this protein-protein interaction could lead to a decrease of LINGO-1 inhibition and an increase in myelination.
authors.affiliation: Department of Cell and Molecular Biology, Vertex Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Jepson
authors.forename: Bryan
authors.initials: B
authors.lastname: Vought
authors.forename: Christian H
authors.initials: CH
authors.lastname: Gross
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: Douglas
authors.initials: D
authors.lastname: Austen
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Frantz
authors.forename: Jacque
authors.initials: J
authors.lastname: Zwahlen
authors.forename: Derek
authors.initials: D
authors.lastname: Lowe
authors.forename: William
authors.initials: W
authors.lastname: Markland
authors.forename: Raul
authors.initials: R
authors.lastname: Krauss
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001369:Axons / Q000378:metabolism; D016466:CHO Cells; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D018920:Coculture Techniques; D006224:Cricetinae; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016086:Lentivirus / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009103:Multiple Sclerosis / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D009457:Neuroglia / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology*
chemical_list: C482293:LINGO1 protein, human; C523678:LINGO1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins