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.
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Du, YZ
Fischer, TZ
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Fischer, TZ
Lee, LN
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Lee, LN
Lercher, LD
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Lercher, LD
Dreyfus, CF
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h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Du, YZ
Fischer, TZ
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h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Fischer, TZ
Clinton-Luke, P
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Clinton-Luke, P
Lercher, LD
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Lercher, LD
Dreyfus, CF
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h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
机构:
Univ Hong Kong, Dept Anat, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China
Univ Hong Kong, State Key Lab Brain & Cognit Sci, Pokfulam, Hong Kong, Peoples R China
Sun Yat Sen Univ, Otorhinolaryngol Hosp, Affiliated Hosp 1, Guangzhou 510275, Guangdong, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Fu, Qing-Ling
Hu, Bing
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机构:
Univ Hong Kong, Dept Anat, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China
Univ Hong Kong, State Key Lab Brain & Cognit Sci, Pokfulam, Hong Kong, Peoples R China
Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Hu, Bing
Li, Xin
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机构:
Sun Yat Sen Univ, Dept Emergency, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Li, Xin
Shao, Zhaohui
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机构:
Biogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USABiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Shao, Zhaohui
Shi, Jian-Bo
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机构:
Sun Yat Sen Univ, Otorhinolaryngol Hosp, Affiliated Hosp 1, Guangzhou 510275, Guangdong, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Shi, Jian-Bo
Wu, Wutian
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机构:
Jinan Univ & Univ Hong Kong, Joint Lab Brain Funct & Hlth, Guangzhou, Guangdong, Peoples R China
Univ Hong Kong, Dept Anat, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China
Univ Hong Kong, State Key Lab Brain & Cognit Sci, Pokfulam, Hong Kong, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Wu, Wutian
So, Kwok-Fai
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机构:
Jinan Univ & Univ Hong Kong, Joint Lab Brain Funct & Hlth, Guangzhou, Guangdong, Peoples R China
Univ Hong Kong, Dept Anat, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China
Univ Hong Kong, State Key Lab Brain & Cognit Sci, Pokfulam, Hong Kong, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
So, Kwok-Fai
Mi, Sha
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机构:
Biogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USABiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Du, YZ
Fischer, TZ
论文数: 0引用数: 0
h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Fischer, TZ
Lee, LN
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h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Lee, LN
Lercher, LD
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h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Lercher, LD
Dreyfus, CF
论文数: 0引用数: 0
h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Du, YZ
Fischer, TZ
论文数: 0引用数: 0
h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Fischer, TZ
Clinton-Luke, P
论文数: 0引用数: 0
h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Clinton-Luke, P
Lercher, LD
论文数: 0引用数: 0
h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
Lercher, LD
Dreyfus, CF
论文数: 0引用数: 0
h-index: 0
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA
机构:
Univ Hong Kong, Dept Anat, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China
Univ Hong Kong, State Key Lab Brain & Cognit Sci, Pokfulam, Hong Kong, Peoples R China
Sun Yat Sen Univ, Otorhinolaryngol Hosp, Affiliated Hosp 1, Guangzhou 510275, Guangdong, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Fu, Qing-Ling
Hu, Bing
论文数: 0引用数: 0
h-index: 0
机构:
Univ Hong Kong, Dept Anat, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China
Univ Hong Kong, State Key Lab Brain & Cognit Sci, Pokfulam, Hong Kong, Peoples R China
Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Hu, Bing
Li, Xin
论文数: 0引用数: 0
h-index: 0
机构:
Sun Yat Sen Univ, Dept Emergency, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Li, Xin
Shao, Zhaohui
论文数: 0引用数: 0
h-index: 0
机构:
Biogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USABiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Shao, Zhaohui
Shi, Jian-Bo
论文数: 0引用数: 0
h-index: 0
机构:
Sun Yat Sen Univ, Otorhinolaryngol Hosp, Affiliated Hosp 1, Guangzhou 510275, Guangdong, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Shi, Jian-Bo
Wu, Wutian
论文数: 0引用数: 0
h-index: 0
机构:
Jinan Univ & Univ Hong Kong, Joint Lab Brain Funct & Hlth, Guangzhou, Guangdong, Peoples R China
Univ Hong Kong, Dept Anat, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China
Univ Hong Kong, State Key Lab Brain & Cognit Sci, Pokfulam, Hong Kong, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
Wu, Wutian
So, Kwok-Fai
论文数: 0引用数: 0
h-index: 0
机构:
Jinan Univ & Univ Hong Kong, Joint Lab Brain Funct & Hlth, Guangzhou, Guangdong, Peoples R China
Univ Hong Kong, Dept Anat, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China
Univ Hong Kong, State Key Lab Brain & Cognit Sci, Pokfulam, Hong Kong, Peoples R ChinaBiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA
So, Kwok-Fai
Mi, Sha
论文数: 0引用数: 0
h-index: 0
机构:
Biogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USABiogen Idec Inc, Discovery Neurobiol Dept, Cambridge, MA USA