Embryonic lethality, decreased erythropoiesis, and defective octamer-dependent promoter activation in Oct-1-deficient mice
Embryonic lethality, decreased erythropoiesis, and defective octamer-dependent promoter activation in Oct-1-deficient mice
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DOI：
10.1128/mcb.24.3.1022-1032.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Tantin, D
中科院分区：
文献类型：
--
作者：
Wang, VEH;Schmidt, T;Tantin, D
Oct-1 是一种序列特异性 DNA 结合转录因子，据信可以调节一大群组织特异性和普遍存在的基因。 Oct-1 和相关但组织限制的 Oct-2 蛋白在体外以相同的亲和力与称为八聚体基序 (5'-ATGCAAAT-3') 的 DNA 序列结合。为了解决 Oct-1 在体内的作用，通过基因打靶产生了 Oct-1 缺陷小鼠品系。 Oct-1缺陷的胚胎在妊娠期间死亡，经常出现贫血，并且缺乏Ter-119阳性红系前体细胞。这种缺陷是细胞固有的。在瞬时转染测定中，源自这些胚胎的成纤维细胞显示 Oct-1 DNA 结合活性显着降低，并且缺乏八聚体依赖性启动子活性。有趣的是，一些被认为受 Oct-1 调节的内源基因的表达没有变化。当与 Oct-2(+/-) 动物杂交时，跨杂合子的恢复频率非常低。这些发现表明 Oct-1 在发育过程中发挥着关键作用，而 Oct-2 在介导产后存活方面具有严格的基因剂量效应。
Oct-1 is a sequence-specific DNA binding transcription factor that is believed to regulate a large group of tissue-specific and ubiquitous genes. Both Oct-1 and the related but tissue-restricted Oct-2 protein bind to a DNA sequence termed the octamer motif (5'-ATGCAAAT-3') with equal affinity in vitro. To address the role of Oct-1 in vivo, an Oct-1-deficient mouse strain was generated by gene targeting. Oct-1-deficient embryos died during gestation, frequently appeared anemic, and suffered from a lack of Ter-119-positive erythroid precursor cells. This defect was cell intrinsic. Fibroblasts derived from these embryos displayed a dramatic decrease in Oct-1 DNA binding activity and a lack of octamer-dependent promoter activity in transient transfection assays. Interestingly, several endogenous genes thought to be regulated by Oct-1 showed no change in expression. When crossed to Oct-2(+/-) animals, transheterozygotes were recovered at a very low frequency. These findings suggest a critical role for Oct-1 during development and a stringent gene dosage effect with Oct-2 in mediating postnatal survival.