Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response
Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response
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DOI：
10.1128/mcb.23.4.1163-1174.2003
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发表时间：
2003-02-01
影响因子：
5.3
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
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作者：
Katsuoka, F;Motohashi, H;Yamamoto, M
小Maf蛋白与CNC和Bach家族蛋白形成异源二聚体，以引起来自Maf识别元件（MARE）的转录响应。我们以前报道过mafG加mafK复合突变小鼠的生殖系靶向缺陷。最突出的突变表型是进行性maf剂量依赖性神经肌肉功能障碍。然而，目前还没有关于小maf基因表达改变对神经功能障碍的影响的报道。我们在这里表明，MafG和MafK在离散的中枢神经系统（CNS）神经元中表达，并且mafG：：mafK化合物突变体显示神经元变性与令人惊讶的选择性MARE依赖性转录异常一致。CNS形态学变化与突变体中神经系统疾病的发作同时发生，并且行为变化伴随着甘氨酸受体亚基积累减少。巴赫/小Maf异源二聚体，通常产生转录抑制因子，显着代表不足，从maf突变体大脑制备的核提取物，巴赫蛋白不能正常积累在细胞核中。因此，化合物mafG：：mafK突变体产生年龄和maf基因剂量依赖性细胞自主神经元缺陷，导致严重的神经缺陷。
The small Maf proteins form heterodimers with CNC and Bach family proteins to elicit transcriptional responses from Maf recognition elements (MAREs). We previously reported germ line-targeted deficiencies in mafG plus mafK compound mutant mice. The most prominent mutant phenotype was a progressive maf dosage-dependent neuromuscular dysfunction. However, there has been no previous report regarding the effects of altered small-maf gene expression on neurological dysfunction. We show here that MafG and MafK are expressed in discrete central nervous system (CNS) neurons and that mafG::mafK compound mutants display neuronal degeneration coincident with surprisingly selective MARE-dependent transcriptional abnormalities. The CNS morphological changes are concurrent with the onset of a neurological disorder in the mutants, and the behavioral changes are accompanied by reduced glycine receptor subunit accumulation. Bach/small Maf heterodimers, which normally generate transcriptional repressors, were significantly under-represented in nuclear extracts prepared from maf mutant brains, and Bach proteins fail to accumulate normally in nuclei. Thus compound mafG::mafK mutants develop age- and maf gene dosage-dependent cell-autonomous neuronal deficiencies that lead to profound neurological defects.