INTRODUCTION: Overcoming remyelination failure in multiple sclerosis (MS) remains a major challenge in the development of effective therapies. Successful remyelination requires the differentiation of oligodendrocyte precursor cells (OPCs), a process that is impaired in MS. Retinoid X receptor gamma (RXRγ), a nuclear receptor known to promote OPC differentiation, is downregulated in MS and this reduction correlates with remyelination failure. However, the precise mechanisms by which RXRγ regulates remyelination, and its potential role in developmental oligodendrogenesis, are still unclear.

AIM(S): We aim to uncover RXRγ role during oligodendrogenesis and its mechanism of action.

METHOD(S): For analyses of RXRg-dependent oligodendrocyte lineage we used new mouse reporter line suitable for cell-fate tracing analyses. To determine functional relevance of RXRg expression in oligodedrogenesis we studied effects of RXRg loss-of-function in RXRg-/- mice using transcriptomic analyses of primary OPCs cultured in vitro or single-nuclei RNA-sequencing (snRNAseq) of corpus callosum samples. Selection of deregulated genes was confirmed using immunofluorescent analyses in mouse brain.

RESULTS: We found that RXRg does not contribute to any major events during pre- or postnatal oligodendrogenesis, but is expressed during regenerative oligodendrogensis associated with aging, or induced in the young adult mouse brain following chemical demyelination. In this context, wild-type, RXRγ-positive OPCs differentiate into mature oligodendrocytes and contribute to remyelination process. In contrast, RXRg-/- exhibit impaired remyelination. Using snRNA-seq we identified a unique molecular signature of RXRg-dependent oligodendrocyte lineage which may directly underlie hypomyelination observed in RXRg-/- brain.

CONCLUSIONS: RXRg is new selective marker and modulator of aging- or disease-associated oligodendrogenesis.

FINANCIAL SUPPORT: France SEP