Smg5 Enhances Oligodendrocyte Differentiation via Nonsense-Mediated mRNA Decay of Hnrnpl Variant Transcripts

Nonsense-mediated mRNA decay (NMD) is a conserved RNA surveillance mechanism that degrades transcripts with premature termination codons (PTCs) and fine-tunes gene expression by targeting RNA transcripts with other NMD inducing features. This study demonstrates that conditional knock-out of Smg5, a key NMD component, in oligodendrocyte lineage cells disrupts the degradation of PTC-containing transcripts, including aberrant variants of the RNA-binding protein Hnrnpl The loss of SMG5 in both sexes of mice impaired oligodendrocyte differentiation, reduced myelin gene expression, and led to thinner myelin sheaths and compromised motor function in mice. Mechanistically, HNRNPL was shown to regulate the alternative splicing of myelin-associated genes Mag and Nfasc and promote oligodendrocyte differentiation. These findings reveal that SMG5-mediated NMD ensures RNA processing fidelity essential for proper oligodendrocyte development and CNS myelination.