A new ENU-induced allele of mouse quaking causes severe CNS dysmyelination

The mutant allelic series of the mouse quaking gene consists of the spontaneous quaking(viable) (qk(v)) allele, which is homozygous viable with a dysmyelination phenotype, and four ENU-induced alleles (qk(kt 1), qk(k2), qk(kt3/4), and qk(l-1)), which are homozygous embryonic lethal. Here we report t...

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Bibliographic Details
Published in:Mammalian genome 2005-09, Vol.16 (9), p.672-682
Main Authors: Noveroske, Janice K, Hardy, Rebecca, Dapper, Jason D, Vogel, Hannes, Justice, Monica J
Format: Article
Language:English
Subjects:
Alleles
Animals
Blotting, Northern
Calbindins
Central Nervous System - ultrastructure
Crosses, Genetic
Demyelinating Diseases - genetics
Demyelinating Diseases - pathology
DNA Primers
Ethylnitrosourea
Immunohistochemistry
Mice
Mice, Quaking
Microscopy, Electron, Transmission
Mutagenesis
Phenotype
RNA-Binding Proteins - genetics
S100 Calcium Binding Protein G
Sequence Analysis, DNA
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Summary:The mutant allelic series of the mouse quaking gene consists of the spontaneous quaking(viable) (qk(v)) allele, which is homozygous viable with a dysmyelination phenotype, and four ENU-induced alleles (qk(kt 1), qk(k2), qk(kt3/4), and qk(l-1)), which are homozygous embryonic lethal. Here we report the isolation of qk(e5), the first ENU-induced viable allele of quaking. Unlike qk(v)/qk(v), qk(e5)/qk(e5) animals have early-onset seizures, severe ataxia, and a dramatically reduced lifespan. Ultrastructural analysis of qk(e5)/qk(e5) brains reveals severe dysmyelination when compared with both wild-type and qk(v)/qk(v) brains. In addition, Calbindin detection in young adult qk(e5)/qk(e5) mice reveals Purkinje cell axonal swellings indicative of neurodegeneration , which is not seen in young adult qk(v)/qk(v) mice. Although the molecular defect in the qk(e5) allele is not evident by sequencing, protein expression studies show that qk(e5)/qk(e5) postnatal oligodendrocytes lack the QKI-6 and QKI-7 isoforms and have reduced QKI-5 levels. The oligodendrocyte developmental markers PDGF alpha R, NG 2, O4, CNP, and MBP are also present in the qk(e5)/qk(e5) postnatal brain although CNP and MBP levels are considerably reduced. Because the qk(v) allele is a large deletion that affects the expression of three genes, the new neurologic qk(e5) allele is an important addition to this allelic series.
ISSN:0938-8990
1432-1777
DOI:10.1007/s00335-005-0035-x