LINGO-1-mediated inhibition of oligodendrocyte differentiation does not require the leucine-rich repeats and is reversed by p75NTR antagonists

• Published in: Molecular and cellular neuroscience Vol. 45; no. 4; pp. 363 - 369
• Main Authors: Bourikas, Dimitris, Mir, Anis, Walmsley, Adrian Robert
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.12.2010
• Subjects: Antagonists; Leucine-rich repeats; LINGO-1; Myelin basic protein; Oligodendrocyte differentiation; p75NTR; PBS; p75NTR; OPC; Oligodendrocyte differentiation; PMA; MS; EAE; CNS; Leucine-rich repeats; LINGO-1; CNPase; LRR; Myelin basic protein; CG4; PDGFRα; FBS; NgR; IB; MBP; GAPDH; Ig
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2010.07.009

LINGO-1 is a potent negative regulator of oligodendrocyte differentiation and hence may play a pivotal restrictive role during remyelination in demyelinating diseases such as multiple sclerosis. However, little is known as to which stages of oligodendrocyte differentiation are inhibited by LINGO-1, which domains of the protein are involved and whether accessory proteins are required. Here, we show that LINGO-1 expression in the human oligodendroglial cell line MO3.13 inhibited process extension and this was reversed by an anti-LINGO-1 antibody or the antagonist LINGO-1-Fc. LINGO-1 expression was also found to inhibit myelin basic protein transcription in the rat oligodendroglial cell line CG4. Both of these inhibitory actions of LINGO-1 were abrogated by deletion of the entire ectodomain or cytoplasmic domains but, surprisingly, were unaffected by deletion of the leucine-rich repeats (LRRs). As in neurons, LINGO-1 physically associated with endogenous p75NTR in MO3.13 cells and, correspondingly, its inhibition of process extension was reversed by antagonists of p75NTR. Thus, LINGO-1 inhibits multiple aspects of oligodendrocyte differentiation independently of the LRRs via a process that requires p75NTR signalling.