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

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Abstract

The mutant allelic series of the mouse quaking gene consists of the spontaneous quakingviable (qkv) allele, which is homozygous viable with a dysmyelination phenotype, and four ENU-induced alleles (qkkt1, qkk2, qkkt3/4, and qkl-1), which are homozygous embryonic lethal. Here we report the isolation of qke5, the first ENU-induced viable allele of quaking. Unlike qkv/qkv, qke5/qke5 animals have early-onset seizures, severe ataxia, and a dramatically reduced lifespan. Ultrastructural analysis of qke5/qke5 brains reveals severe dysmyelination when compared with both wild-type and qkv/qkv brains. In addition, Calbindin detection in young adult qke5/qke5 mice reveals Purkinje cell axonal swellings indicative of neurodegeneration , which is not seen in young adult qkv/qkv mice. Although the molecular defect in the qke5 allele is not evident by sequencing, protein expression studies show that qke5/qke5 postnatal oligodendrocytes lack the QKI-6 and QKI-7 isoforms and have reduced QKI-5 levels. The oligodendrocyte developmental markers PDGFαR, NG2, O4, CNP, and MBP are also present in the qke5/qke5 postnatal brain although CNP and MBP levels are considerably reduced. Because the qkv allele is a large deletion that affects the expression of three genes, the new neurologic qke5 allele is an important addition to this allelic series.

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Acknowledgments

The authors thank Karen Artzt and Neil Box for providing antibodies and Diego Lorenzetti for critical reading of the manuscript. This work was supported by grants from the Kleberg Foundation, and from Public Health Service Grant U01 HD39372 to MJJ.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, S413, Houston, Texas, 77030, USA

    Janice K. Noveroske, Jason D. Dapper & Monica J. Justice

  2. Department of Cellular & Molecular Neuroscience (Neuroscience), Imperial College London, Charing Cross Hospital Campus, Fulham Palace Road, London, W6 8RF, United Kingdom

    Rebecca Hardy

  3. Department of Pathology (Neuropathology), Stanford University Medical Center, R241, 300 Pasteur Drive, Stanford, California, 94305, USA

    Hannes Vogel

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  1. Janice K. Noveroske
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  2. Rebecca Hardy
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  5. Monica J. Justice
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Correspondence to Monica J. Justice.

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Noveroske, J.K., Hardy, R., Dapper, J.D. et al. A new ENU-induced allele of mouse quaking causes severe CNS dysmyelination. Mamm Genome 16, 672–682 (2005). https://doi.org/10.1007/s00335-005-0035-x

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