The quakingviable mutation affects qkl mRNA expression specifically in myelin-producing cells of the nervous system

Abstract

The genetic lesion in the quakingviable (qkv) mutant mice is a deletion 5′ to the qkI gene, resulting in severe hypomyelination. qkI produces several QKI protein isoforms via alternative splicing of the C-terminal coding exons. In the qkv/qkv brain, immunostaining of QKI proteins is diminished in an isoform-differential manner with undefined mechanisms. We examined the expression of QKI protein isoforms and qkI mRNA isoforms in the qkv/qkv mutants and the non-phenotypic wt/qkv littermates. Our results indicated significant reduction of all qkI mRNA isoforms in the central and peripheral nervous system during active myelination without detectable post-transcriptional abnormalities. In the early stage of myelin development, qkI mRNAs are differentially reduced, which appeared to be responsible for the reduction of the corresponding QKI protein isoforms. The reduced qkI expression was a specific consequence of the qkv lesion, not observed in other hypomyelination mutants. Furthermore, no abnormal qkI expression was found in testis, heart and astroglia of the qkv/qkv mice, suggesting that the reduction of qkI mRNAs occurred specifically in myelin-producing cells of the nervous system. These observations suggest that diminished qkI expression results from deletion of an enhancer that promotes qkI transcription specifically in myelinating glia during active myelinogenesis.