biostudies-literatureBuscham TJDeutsche ForschungsgemeinschaftEuropean Research CouncilWellcome Truste75523https://www.ebi.ac.uk/biostudies/studies/S-EPMC8916772biostudies-literatureUnknown11Oligodendrocytes 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.eLifeProgressive axonopathy when oligodendrocytes lack the myelin protein CMTM5.PMC8916772Advanced Grant MyeliNanoWE 2720/2-2WE 2720/4-1WE 2720/5-1Steyer AMBoretius SJahn OBuscham TJStrenzke NSiems SBDardawal RSun TNave KAEichel-Vogel MAMemhave TRWerner HBMuller CMobius WRuhwedel TMeschkat MKramer-Albers EMfalseProgressive axonopathy when oligodendrocytes lack the myelin protein CMTM5.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.2022-01-01T00:00:00Z2022 Mar2026-05-31T05:00:23.451Z2026-04-08T08:10:10.803ZS-EPMC89167723527461510.7554/eLife.75523