Switching on pluripotency: a perspective on the biological requirement of Nanog

Pluripotency is a transient cellular state during early development which can be recreated in vitro by direct reprogramming. The molecular mechanisms driving entry into and exit from the pluripotent state are the subject of intense research interest. Here, we review the role of the homeodomain-containing transcription factor Nanog in mammalian embryology and induced pluripotency. Nanog was originally thought to be confined to the maintenance of pluripotency, but recent insights from genetic studies uncovered a new biological function. Embryonic stem cells deficient in Nanog alleles are more prone to differentiate but do not lose pluripotency per se. Instead, Nanog is transiently required for the specification of the naive pluripotent epiblast and development of primordial germ cells. Nanog is also essential to finalize somatic cell reprogramming during induction of pluripotency. We propose that this unique transcription factor acts as a molecular switch to turn on the naive pluripotent programme in mammalian cells. In this context, the capacity of Nanog to resist differentiation can be regarded as recapitulation of effects normally associated with the specification of pluripotency. Pertinent questions are how Nanog specifies naive pluripotency and whether this mechanism is evolutionarily conserved.