LINGO-1, a Transmembrane Signaling Protein, Inhibits Oligodendrocyte Differentiation and Myelination through Intercellular Self-interactions

被引:83
作者
Jepson, Scott [1 ]
Vought, Bryan [2 ]
Gross, Christian H. [3 ]
Gan, Lu [2 ]
Austen, Douglas [2 ]
Frantz, J. Daniel [1 ]
Zwahlen, Jacque [2 ]
Lowe, Derek [4 ]
Markland, William [1 ]
Krauss, Raul [1 ]
机构
[1] Vertex Pharmaceut Inc, Dept Cell & Mol Biol, Cambridge, MA 02139 USA
[2] Vertex Pharmaceut Inc, Dept Prot Sci, Cambridge, MA 02139 USA
[3] Vertex Pharmaceut Inc, Dept Enzymol, Cambridge, MA 02139 USA
[4] Vertex Pharmaceut Inc, Dept Chem Res, Cambridge, MA 02139 USA
关键词
CENTRAL-NERVOUS-SYSTEM; RECEPTOR FAMILY-MEMBER; PRECURSOR CELLS; NOGO RECEPTOR; REMYELINATION; ASTROCYTES; EXPRESSION; BDNF;
D O I
10.1074/jbc.M112.366179
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:22184 / 22195
页数:12
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