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Cerebellar pathology in transgenic mice expressing the pseudorabies virus immediate-early protein IE180

Authors

  • Yukiko Tomioka,

    1. Laboratory of Animal Experiment for Disease Model, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
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    • *

      Y.T. and T.M. contributed equally to this work.

  • Taisuke Miyazaki,

    1. Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
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    • *

      Y.T. and T.M. contributed equally to this work.

  • Satoshi Taharaguchi,

    1. Laboratory of Animal Experiment for Disease Model, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
    2. Laboratory of Veterinary Microbiology, Department of Veterinary Medicine, Faculty of Agriculture, Kagoshima University, Kagoshima, Japan
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  • Saori Yoshino,

    1. Gene Techno Science, Sapporo, Japan
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  • Masami Morimatsu,

    1. Laboratory of Animal Experiment for Disease Model, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
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  • Toshimitsu Uede,

    1. Division of Molecular Immunology, Research Section of Molecular Pathogenesis, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
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  • Etsuro Ono,

    1. Laboratory of Animal Experiment for Disease Model, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
    2. The Avian Zoonoses Research Center, Faculty of Agriculture, Tottori University, Tottori, Japan
    3. Laboratory of Biomedicine, Center of Biomedical Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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  • Masahiko Watanabe

    1. Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
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Dr Etsuro Ono, 7Laboratory of Biomedicine, as above.
E-mail: etsuro@qda.med.kyushu-u.ac.jp
Dr Masahiko Watanabe, as above.
E-mail: watamasa@med.hokudai.ac.jp

Abstract

Pseudorabies virus is an alphaherpesvirus causing fatal neurological diseases in animals. Pseudorabies virus carries a gene encoding immediate-early (IE) protein IE180, which controls the transcription of other viral and host cell genes. Previously, we reported that transgenic expression of IE180 in mice causes severe ataxia and cerebellar deformity. Here we identified profound abnormalities in adult IE180 transgenic mice, including malpositioning of Purkinje cells (PCs), granule cells (GCs) and Bergmann glia (BG), impaired dendritogenesis and synaptogenesis in PCs, disoriented BG fibers, absence of molecular layer interneurons, and increased apoptosis of neurons and glia. In accordance with the cellular defects, we found the expression of IE180 in PCs, GCs and astrocytes during cerebellar development. We next examined transgenic mice expressing truncated IE180 mutants: dlN132 lacking the acidic transcriptional active domain, dlC629 lacking the nuclear localization signal and dlC1081 having all known domains but lacking the carboxyl-terminal sequence. Despite similar expression levels of the transgenes, ataxia and cerebellar defects were only manifested in the dlC1081 transgenic mice but their phenotypes were milder compared with the IE180 transgenic mice. In the dlC1081 transgenic mice, cerebellar neurons and glia were normally positioned but cerebellar size was severely reduced due to GC deficits. Interestingly, dlC1081 was mainly expressed in the GCs with low expression in a few BG. Taken together, the present findings clarified a causal relationship between cerebellar pathology and cellular expression of IE180, and further afforded an experimental insight into different symptomatic severity as a consequence of different cellular defects caused by such cytotoxic viral agents.

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