Central nervous system-specific deletion of transcription factor Nrf1 causes progressive motor neuronal dysfunction
Central nervous system-specific deletion of transcription factor Nrf1 causes progressive motor neuronal dysfunction
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DOI：
10.1111/j.1365-2443.2011.01522.x
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发表时间：
2011-06-01
期刊：
影响因子：
2.1
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
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作者：
Kobayashi, Akira;Tsukide, Takako;Yamamoto, Masayuki
Cap'n'Collar (CNC) 蛋白与小 Maf 蛋白异二聚化并调节各种基因的转录。小型 Maf 缺陷小鼠会出现严重的神经退行性变，目前尚不清楚 CNC 蛋白是否参与了这一过程。在这项研究中，我们研究了 CNC 蛋白之一 Nrf1 对体内神经元稳态的贡献。由于 Nrf1 基因敲除小鼠具有胚胎致死性，因此我们使用携带 Nrf1flox 等位基因和 Nestin-Cre 等位基因的小鼠开发了中枢神经系统 (CNS) 特异性 Nrf1 敲除 (CKO) 小鼠系。出生时，CKO 小鼠与对照小鼠没有什么区别，但此后它们表现出进行性运动共济失调和严重的体重减轻。所有 Nrf1 CKO 小鼠均在 3 周内死亡。这些表型与小型 Maf 缺陷小鼠中报道的相似，表明 Nrf1 和小型 Maf 蛋白之间存在协作。我们还发现 Nrf1 CKO 小鼠中枢神经系统各个区域中多聚泛素化蛋白的异常积累以及海马中明显的神经元损失。小鼠脊髓中积累了氧化应激标志物，但Nrf2调控的氧化应激反应基因的表达模式没有显着变化。这些结果表明，Nrf1 通过调节与 Nrf2 调节的靶基因不同的靶基因来维持 CNS 稳态。
Cap'n'Collar (CNC) proteins heterodimerize with small Maf proteins and regulate the transcription of various genes. Small Maf-deficient mice develop severe neurodegeneration, and it remains unclear whether CNC proteins are involved in this process. In this study, we examined the contribution of Nrf1, one of the CNC proteins, to neuronal homeostasis in vivo. As Nrf1 gene knockout mice are embryonic lethal, we developed a central nervous system (CNS)-specific Nrf1 knockout (CKO) mouse line using mice bearing an Nrf1flox allele and Nestin-Cre allele. At birth, the CKO mice appeared indistinguishable from control mice, but thereafter they showed progressive motor ataxia and severe weight loss. All Nrf1 CKO mice died within 3 weeks. These phenotypes are similar to those reported in small Maf-deficient mice, suggesting the presence of collaboration between Nrf1 and small Maf proteins. We also found aberrant accumulation of polyubiquitinated proteins in various CNS regions and apparent neuronal loss in the hippocampus of Nrf1 CKO mice. An oxidative stress marker was accumulated in the spinal cords of the mice, but the expression patterns of oxidative stress response genes regulated by Nrf2 did not change substantially. These results show that Nrf1 sustains the CNS homeostasis through regulating target genes distinct from those regulated by Nrf2.