Nanog safeguards pluripotency and mediates germline development

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Abstract
In 2003 the transcription factor Nanog was identified as a key contributor to the property that makes embryonic stem cells unique: pluripotency. Nanog, named after Tir nan Og, the 'land of the forever-young' of Celtic myth, was thought to be required for stem cells to multiply while retaining the potential to differentiate. New work in mouse embryonic stem cells suggests a rather different picture. In fact Nanog is not essential for maintaining pluripotency; its levels fluctuate, but Nanog appears to stabilize the pluripotent state by resisting or reversing alternative states of gene expression. The transcription factor Nanog is considered a hallmark of pluripotent cells in vivo and in vitro, and loss of Nanog an early marker of differentiation. This is now revised by the demonstration that Nanog is not essential for maintaining pluripotency, but acts in stabilizing the pluripotent state. Nanog is a divergent homeodomain protein found in mammalian pluripotent cells and developing germ cells1,2. Deletion of Nanog causes early embryonic lethality2, whereas constitutive expression enables autonomous self-renewal of embryonic stem cells1. Nanog is accordingly considered a core element of the pluripotent transcriptional network3,4,5,6,7. 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.