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

Abstract

The genetic lesion in the quakingviable (qk(v)) 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 qk(v)/qk(v) 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 qk(v)/qk(v) mutants and the non-phenotypic wt/qk(v) 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 qk(v) lesion, not observed in other hypomyelination mutants. Further more, no abnormal qkI expression was found in testis, heart and astroglia of the qk(v)/qk(v) 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.

Rescuing qkvDysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI

“…Homozygous qk v mutants suffer from diminished expression of myelin structural proteins and severe hypomyelination (Sidman et al, 1964;Hogan and Greenfield, 1984;Hardy, 1998). The qk v mutation deletes an enhancer of the qkI gene and causes diminished qkI transcription specifically in myelin-producing cells (Hardy et al, 1996;Lu et al, 2003), which is postulated as the cause for dysmyelination (Hardy, 1998;McInnes and Lauriat, 2006). Three major QKI protein isoforms, designated as QKI-5, QKI-6, and QKI-7, are expressed in glia but absent in neurons (Hardy et al, 1996;Kondo et al, 1999).…”

Deletion of the Parkin coregulated gene causes male sterility in the quaking viable mouse mutant

“…The qk gene, which encodes for RNA binding proteins involved in posttranscriptional mRNA regulation (6,7), is in close proximity to the proximal deletion breakpoint of qk v (8). The qk v deficiency affects the region upstream of the qk gene to reduce the expression of qk mRNAs in oligodendrocytes, resulting in the CNS myelination defect (9,10). In addition to the spontaneous qk v deletion, several N-ethyl-N-nitrosourea (ENU)-induced alleles of quaking have been isolated (11)(12)(13).…”

Regulation of Cellular MicroRNA Expression in Oligodendrocytes during Acute and Persistent Coronavirus Infection

“…miR-214 has predicted targets at the 3'-UTR of Quaking (Gk) gene [40]. There are 3 isoforms of Qk gene, whose expression is related to the CNS demyelination disease of mice (quaking mice, as also seen in shivering mice) [41][42][43][44][45][46].miR-129-5p targets two transcriptional repressors of myelin-specific genes, SCIP (POU3F1) and Brn-2 (POU3F2), which repress myelin-specific gene expression. Both transcription factors were also significantly up-regulated during coronavirus persistence in a rat oligodendrocyte CG-4 cell line [47] and during acute and persistent infection in mouse oligodendrocytic N20.1 cells ( Figure 4D).…”