Progressive axonopathy when oligodendrocytes lack the myelin protein CMTM5.

Abstract

Oligodendrocytes facilitate rapid impulse propagation along the axons they myelinate and support their long-term integrity. However, the functional relevance of many myelin proteins has remained unknown. Here, we find that expression of the tetraspan-transmembrane protein CMTM5 (chemokine-like factor-like MARVEL-transmembrane domain containing protein 5) is highly enriched in oligodendrocytes and central nervous system (CNS) myelin. Genetic disruption of the <i>Cmtm5</i> gene in oligodendrocytes of mice does not impair the development or ultrastructure of CNS myelin. However, oligodendroglial <i>Cmtm5</i> deficiency causes an early-onset progressive axonopathy, which we also observe in global and tamoxifen-induced oligodendroglial <i>Cmtm5</i> mutants. Presence of the <i>Wld^S</i> mutation ameliorates the axonopathy, implying a Wallerian degeneration-like pathomechanism. These results indicate that CMTM5 is involved in the function of oligodendrocytes to maintain axonal integrity rather than myelin biogenesis.