Nanog safeguards pluripotency and mediates germline development
Nanog safeguards pluripotency and mediates germline development
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DOI：
10.1038/nature06403
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发表时间：
2007-12-20
期刊：
影响因子：
64.8
通讯作者：
Smith, Austin
中科院分区：
文献类型：
--
作者：
Chambers, Ian;Silva, Jose;Smith, Austin
Nanog是一种在哺乳动物多能细胞和发育中的生殖细胞中发现的独特同源结构域蛋白（1,2）。Nanog的缺失会导致早期胚胎致死（2），而组成性表达使胚胎干细胞能够自主自我更新（1）。因此，Nanog被认为是多能转录网络的核心要素（3 - 7）。然而，在此我们报道Nanog在小鼠胚胎干细胞中是波动的。Nanog的瞬时下调似乎使细胞倾向于分化，但并不标志着细胞分化的定型。通过基因缺失我们表明，尽管胚胎干细胞容易分化，但在Nanog永久缺失的情况下它们能够无限地自我更新。扩增的Nanog缺失细胞可在胚胎胚层中定植，并在胎儿和成年嵌合体中表现出多谱系分化。尽管它们也会被募集到生殖系，但缺乏Nanog的原始生殖细胞在到达生殖嵴时无法成熟。这种缺陷可通过修复突变等位基因来挽救。因此，Nanog对于体细胞多能性的表达是可有可无的，但对于生殖细胞的形成是特别必需的。因此，Nanog主要在构建内细胞团和生殖细胞状态中起作用，而不是在多能性的维持机制中起作用。我们推测Nanog通过抵抗或逆转其他基因表达状态来稳定培养中的胚胎干细胞。
Nanog is a divergent homeodomain protein found in mammalian pluripotent cells and developing germ cells(1,2). Deletion of Nanog causes early embryonic lethality(2), whereas constitutive expression enables autonomous self- renewal of embryonic stem cells(1). Nanog is accordingly considered a core element of the pluripotent transcriptional network(3-7). However, here we report that Nanog fluctuates in mouse embryonic stem cells. Transient downregulation of Nanog appears to predispose cells towards differentiation but does not mark commitment. By genetic deletion we show that, although they are prone to differentiate, embryonic stem cells can self- renew indefinitely in the permanent absence of Nanog. Expanded Nanog null cells colonize embryonic germ layers and exhibit multilineage differentiation both in fetal and adult chimaeras. Although they are also recruited to the germ line, primordial germ cells lacking Nanog fail to mature on reaching the genital ridge. This defect is rescued by repair of the mutant allele. Thus Nanog is dispensible for expression of somatic pluripotency but is specifically required for formation of germ cells. Nanog therefore acts primarily in construction of inner cell mass and germ cell states rather than in the housekeeping machinery of pluripotency. We surmise that Nanog stabilizes embryonic stem cells in culture by resisting or reversing alternative gene expression states.