Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1
Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1
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DOI：
10.1074/jbc.m311347200
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发表时间：
2004-02-06
影响因子：
4.8
通讯作者：
Seeburg, PH
中科院分区：
文献类型：
--
作者：
Hartner, JC;Schmittwolf, C;Seeburg, PH
ADAR1（作用于RNA-1的腺苷脱氨酶）在哺乳动物中广泛表达，但其生物学作用尚不清楚。我们在此通过基因靶向表明，ADAR1 在体内选择性编辑神经组织血清素 5-羟色胺亚型 2C 受体前体 mRNA 中五个紧密排列的腺苷中的两个；因此，位点选择性腺苷至肌苷编辑确实是 ADAR1 的功能。值得注意的是，ADAR1 的两个不同无效等位基因的纯合性导致在胚胎第 11 天早期出现一致的胚胎表型，并导致胚胎第 11.5 至 12.5 天之间死亡。这种表型表现出肝脏结构迅速崩解，同时伴有明确造血功能的严重缺陷，包括红系和髓样/颗粒样祖细胞以及来自主动脉-性腺-中肾区域和胎儿肝脏的脾集落形成活性。可能由于这些发育障碍，ADAR1缺陷的胚胎干细胞无法对成年嵌合小鼠的肝脏、骨髓、脾脏、胸腺和血液做出贡献。因此，ADAR1 促进非神经组织发育的关键步骤，其中可能包括转录编辑。
ADAR1 (adenosine deaminase acting on RNA-1) is widely expressed in mammals, but its biological role is unknown. We show here by gene targeting that ADAR1 selectively edits in vivo two of five closely spaced adenosines in the serotonin 5-hydroxytryptamine subtype 2C receptor pre-mRNA of nervous tissue; and hence, site-selective adenosine-to-inosine editing is indeed a function of ADAR1. Remarkably, homozygosity for two different null alleles of ADAR1 caused a consistent embryonic phenotype appearing early at embryonic day 11 and leading to death between embryonic days 11.5 and 12.5. This phenotype manifests a rapidly disintegrating liver structure, along with severe defects in definitive hematopoiesis, encompassing both erythroid and myeloid/granuloid progenitors as well as spleen colony-forming activity from the aorta-gonad-mesonephros region and fetal liver. Probably as a consequence of these developmental impairments, ADAR1-deficient embryonic stem cells failed to contribute to liver, bone marrow, spleen, thymus, and blood in adult chimeric mice. Thus, ADAR1 subserves critical steps in developing non-nervous tissue, which are likely to include transcript editing.