Perinatal synthetic lethality and hematopoietic defects in compound mafG::mafK mutant mice
Perinatal synthetic lethality and hematopoietic defects in compound mafG::mafK mutant mice
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DOI：
10.1093/emboj/19.6.1335
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发表时间：
2000-03
期刊：
影响因子：
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通讯作者：
K. Onodera;J. Shavit;H. Motohashi;Masayuki Yamamoto;J. D. Engel
中科院分区：
文献类型：
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作者：
K. Onodera;J. Shavit;H. Motohashi;Masayuki Yamamoto;J. D. Engel
探索控制红细胞基因调控的机制的先前研究暗示MARE（Maf识别元件）顺式元件对许多红细胞基因的转录活性至关重要。许多转录因子可以通过MARE引发反应，不仅包括AP-1家族蛋白，还包括越来越多的由Cap-N-Collar（CNC）-小Maf异二聚体组成的因子。虽然这些因子可以在共转染试验中激活MARE的转录，但迄今为止测试的cnc基因中的小鼠种系突变未能揭示初级红细胞表型。在这里，我们报告，结合mafK和mafG靶向无效等位基因后，突变动物显示几种合成表型，包括红细胞缺陷。首先，复合纯合小maf基因突变体在胚胎发生中存活，但在出生后死亡。第二，复合突变动物会出现严重的神经系统疾病。第三，它们在巨核细胞生成中，特别是在前血小板形成中表现出加剧的mafG缺乏，导致严重的血小板减少症。最后，复合突变动物发展严重贫血，伴有异常的红细胞形态和膜蛋白组成。这些数据为小Maf转录因子在红细胞生成中发挥重要的调节作用提供了直接证据。
Prior studies exploring the mechanisms controlling erythroid gene regulation implicated MARE (Maf recognition element) cis‐elements as crucial to the transcriptional activity of many erythroid genes. Numerous transcription factors can elicit responses through MAREs, including not only the AP‐1 family proteins, but also a growing list of factors composed of Cap‐N‐Collar (CNC)–small Maf heterodimers. While these factors can activate transcription from MAREs in co‐transfection assays, mouse germline mutations in cnc genes tested to date have failed to reveal primary erythroid phenotypes. Here we report that after combining the mafK and mafG targeted null alleles, mutant animals display several synthetic phenotypes, including erythroid deficiencies. First, compound homozygous small maf gene mutants survive embryogenesis, but die postnatally. Secondly, compound mutant animals develop severe neurological disorders. Thirdly, they exhibit an exacerbated mafG deficiency in megakaryopoiesis, specifically in proplatelet formation, resulting in profound thrombocytopenia. Finally, the compound mutant animals develop severe anemia accompanied by abnormal erythrocyte morphology and membrane protein composition. These data provide direct evidence that the small Maf transcription factors play an important regulatory role in erythropoiesis.