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 differentiation in vitro and remyelination in vivo Furthermore, 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 STATEMENT Myelin 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.