Chambers Ian, Silva Jose, Colby Douglas, Nichols Jennifer, Nijmeijer Bianca, Robertson Morag, Vrana Jan, Jones Ken, Grotewold Lars, Smith Austin
MRC Centre Development in Stem Cell Biology, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JQ, UK.
Nature. 2007 Dec 20;450(7173):1230-4. doi: 10.1038/nature06403.
Nanog is a divergent homeodomain protein found in mammalian pluripotent cells and developing germ cells. Deletion of Nanog causes early embryonic lethality, whereas constitutive expression enables autonomous self-renewal of embryonic stem cells. Nanog is accordingly considered a core element of the pluripotent transcriptional network. 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.
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不同寻常的同源结构域蛋白。Nanog的缺失会导致早期胚胎致死，而组成型表达则能使胚胎干细胞实现自主自我更新。因此，Nanog被认为是多能转录网络的核心元件。然而，我们在此报告，Nanog在小鼠胚胎干细胞中存在波动。Nanog的短暂下调似乎会使细胞易于分化，但并不标志着细胞已确定分化方向。通过基因敲除我们发现，尽管胚胎干细胞易于分化，但在永久缺失Nanog的情况下仍能无限期自我更新。经扩增的Nanog基因敲除细胞可定殖于胚胎胚层，并在胎儿和成年嵌合体中表现出多谱系分化。尽管缺乏Nanog的原始生殖细胞也会被募集到生殖系，但它们在到达生殖嵴时无法成熟。通过修复突变等位基因可挽救这一缺陷。因此，Nanog对于体细胞多能性的表达并非必需，但对于生殖细胞的形成却是特别需要的。所以，Nanog主要作用于内细胞团和生殖细胞状态的构建，而非多能性的维持机制。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。
