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Loss of WT1 gene in neuron and glia affects the phenotypes of Huntington’s disease model mice

  • P3-303
  • 横山 翔平 / Shohei Yokoyama:1 播磨 篤 / Atsushi Harima:1 上村 佳子 / Keiko Kamimura:1 武田 雄希 / Yuuki Takeda:1 鈴木 耀 / Koyo Suzuki:1 幸田 敏明 / Toshiaki Koda:1 
  • 1:北海道大院生命 / Graduate School of Life Science, Univ of Hokkaido, Hokkaido, Japan 

Huntington's disease (HD) is a chronic progressive neurodegenerative disorder characterized by choreiform movements. HD is caused by an abnormally expanded CAG repeat (over 35) within the coding region of the huntingtin gene (htt). Aggregates of the abnormal HTT protein cause cytotoxicity and apoptosis in neuron especially in striata, thereby representing involuntary movement or motor incoordination. In the previous studies of our lab, we have shown marked increase in expression of Wilms' tumor 1 (WT1) gene in striata of HD model mice. Since WT1 gene was suggested to play roles in apoptosis of neurons in Alzheimer's disease, we hypothesized that WT1 may also play roles in apoptosis of neurons in HD. To examine this possibility, we first investigated the effects of the absence of WT1 gene in neuron using Synapsin-Cre WT1-knockout HD model mice (R6/2). However, there were no significant differences in the progression of the disease. In the course of examination of these model mice, we found the expression levels of WT1 in striata of WT1-knockout R6/2 mice are almost the same as WT1-wildtype R6/2 mice at the early stages. It suggested that induction of WT1 at juvenile period mainly occurred in glial cells, and this was sufficient for subsequent pathological process.
In this study, we used Nestin-Cre conditional knockout mice, in which WT1 was knocked out in neuron and glial cells, to examine if the induction of WT1 in glial cells affects onset of HD. Specifically, we run successive trials of motor performance in mice and compared the results between WT1-knockout and wild type R6/2 mice. Here we found exacerbation of HD phenotype by deleting WT1 gene. This suggests that in this HD model, induction of WT1 does not promote apoptosis, but rather play some protective roles on neuron. Currently, we are investigating neuroprotective roles of WT1-expressing glial cells in an in vitro culture system.

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