Effects of thioredoxin reductase-1 deletion on embryogenesis and transcriptome
Effects of thioredoxin reductase-1 deletion on embryogenesis and transcriptome
复制标题
DOI：
10.1016/j.freeradbiomed.2007.05.026
复制
发表时间：
2007-09-15
影响因子：
7.4
通讯作者：
Schmidt, Edward E.
中科院分区：
文献类型：
--
作者：
Bondareva, Alla A.;Capecchi, Mario R.;Schmidt, Edward E.
硫氧还蛋白还原酶(Txnrd)在大多数生物体中维持细胞内氧化还原动态平衡。后生动物Txnrds也参与信号转导。编码胞浆硫氧还蛋白还原酶的tynrd1基因的定向零突变纯合子的小鼠胚胎在胚胎8.5天(E8.5)时是活的，但在E9.5天时就不是了。组织学显示，txnrdl(-/-)细胞能够增殖和分化，但突变的胚胎比野生型小，不能原肠形成。原位标记基因分析表明，未形成原始条纹中胚层。对e7.5txnrd(-/-)和txnrd(+/+)的基因芯片分析显示，过氧化还蛋白、谷胱甘肽还原酶、线粒体Txnrd2和大多数细胞增殖标志的mRNA水平相似。相反，编码后氧化还蛋白、胰岛素样生长因子结合蛋白1、羰基还原酶3、谷氨酸半胱氨酸连接酶、谷胱甘肽S转移酶和金属硫蛋白的mRNAs在突变体中更为丰富。许多基因表达反应与硫氧还蛋白还原酶1缺失酵母中的基因表达反应相似；然而，小鼠在过氧化还蛋白催化循环中表现出一种新的反应。因此，酵母在硫氧还蛋白还原酶中断时诱导过氧化还蛋白mRNAs，而小鼠则诱导硫氧还蛋白mRNAs。综上所述，Txnrd1对于早期胚胎的正确构型和后期发育是必需的。对Txnrd1中断的保守反应可能允许突变胚胎细胞的增殖和有限的分化。(C)2007 Elsevier Inc.保留所有权利。
Thioredoxin reductases (Txnrd) maintain intracellular redox homeostasis in most organisms. Metazoan Txnrds also participate in signal tramsduction. Mouse embryos homozygous for a targeted null mutation of the tynrd1 gene, encoding the cytosolic thioredoxin reductase, were viable at embryonic day 8.5 (E8.5) but not at E9.5. Histology revealed that txnrdl(-/-) cells were capable of proliferation and differentiation,- however, inutant embryos were smaller than wild-type littermates and failed to gastrulate. In situ marker gene analyses indicated that primitive streak mesoderm did not form. Microarray analyses on E7.5 txnrd(-/-) and txnrd(+/+) littermates showed similar mRNA levels for peroxiredoxins, glutathione reductases, rnitochondrial Txnrd2, and most markers of cell proliferation. Conversely, mRNAs encoding suffiredoxin, IGF-binding protein 1, carbonyl reductase 3, glutamate cysteine ligase, glutathione S-transferases, and metallothioneins were more abundant in mutants. Many gene expression responses murrored those in thioredoxin reductase 1-null yeast; however, mice exhibited a novel response within the peroxiredoxin catalytic cycle. Thus, whereas yeast induce peroxiredoxin mRNAs in response to thioredoxin reductase disruption, mice induced sulfiredoxin mRNA. In summary, Txnrd1 was required for correct patterning of the early embryo and progression to later development. Conserved responses to Txnrd1 disruption likely allowed proliferation and limited differentiation of the mutant embryo cells. (c) 2007 Elsevier Inc. All rights reserved.