title: LINGO-1 Regulates Oligodendrocyte Differentiation through the Cytoplasmic Gelsolin Signaling Pathway.
abstract: Differentiation and maturation of oligodendrocyte progenitor cells (OPCs) involve the assembly and disassembly of actin microfilaments. However, how actin dynamics are regulated during this process remains poorly understood. Leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1 (LINGO-1) is a negative regulator of OPC differentiation. We discovered that anti-LINGO-1 antibody-promoted OPC differentiation was accompanied by upregulation of cytoplasmic gelsolin (cGSN), an abundant actin-severing protein involved in the depolymerization of actin filaments. Treating rat OPCs with cGSN siRNA reduced OPC differentiation, whereas overexpression of cGSN promoted OPC differentiationin vitroand remyelinationin vivoFurthermore, coexpression of cGSN and LINGO-1 blocked the inhibitory effect of LINGO-1. Our study demonstrates that cGSN works downstream of LINGO-1 signaling pathway, which enhances actin dynamics and is essential for OPC morphogenesis and differentiation. This finding may lead to novel therapeutic approaches for the treatment of demyelinating diseases such as multiple sclerosis (MS).SIGNIFICANCE STATEMENTMyelin loss and subsequent axon degeneration contributes to a variety of neurological diseases, such as multiple sclerosis (MS). Understanding the regulation of myelination by oligodendrocytes is therefore critical for developing therapies for the treatment of MS. We previously demonstrated that leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1 (LINGO-1) is a negative regulator of oligodendrocyte differentiation and that anti-LINGO-1 promotes remyelination in preclinical animal models for MS and in a phase II acute optic neuritis clinical trial (RENEW). The mechanism by which LINGO-1 regulates oligodendrocyte differentiation is unknown. Here, we demonstrate that LINGO-1 regulates oligodendrocyte differentiation and maturation through the cytoplasmic gelsolin signaling pathway, providing new drug targets for the treatment of demyelination diseases.
authors.affiliation: Biogen, Inc., Cambridge, Massachusetts 02142.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Biogen, Inc., Cambridge, Massachusetts 02142.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Lee
authors.affiliation: Biogen, Inc., Cambridge, Massachusetts 02142.
authors.forename: Guanrong
authors.initials: G
authors.lastname: Huang
authors.affiliation: Biogen, Inc., Cambridge, Massachusetts 02142.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Sheng
authors.affiliation: Biogen, Inc., Cambridge, Massachusetts 02142.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Henderson
authors.affiliation: Biogen, Inc., Cambridge, Massachusetts 02142.
authors.forename: Daniel
authors.identifier: 0000-0001-5956-7755
authors.initials: D
authors.lastname: Louvard
authors.affiliation: Biogen, Inc., Cambridge, Massachusetts 02142.
authors.forename: Jiho
authors.initials: J
authors.lastname: Sohn
authors.affiliation: Biogen, Inc., Cambridge, Massachusetts 02142.
authors.forename: Blake
authors.initials: B
authors.lastname: Pepinsky
authors.affiliation: Biogen, Inc., Cambridge, Massachusetts 02142 sha.mi@biogen.com.
authors.forename: Sha
authors.identifier: 0000-0002-4786-6894
authors.initials: S
authors.lastname: Mi
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D018260:Gelsolin / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000199:Actins; D018260:Gelsolin; C523678:LINGO1 protein, mouse; C525164:LINGO1 protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins
keywords: LINGO-1; cytoplasmic gelsolin; multiple sclerosis; oligodendrocyte; remyelination; therapeutic