The establishment of pluripotency during mouse embryogenesis and during the reprogramming of somatic cells is dependent on the homeodomain-containing transcription factor Nanog but, puzzlingly, compared with other pluripotency-associated genes, Nanog is poorly conserved among vertebrates. Here (), José Silva, Filipe Castro and colleagues investigate whether Nanog orthologues can orchestrate pluripotency in Nanog–/– mouse somatic cells. Surprisingly, the researchers report that mammalian, avian and teleost Nanog orthologues all reprogramme mouse Nanog-/- somatic cells to full pluripotency, despite sharing as little as 13% sequence identity with mouse Nanog. Moreover, they identify two unique residues in the DNA recognition helix of the Nanog homeodomain that are important for reprogramming and show that the Nanog homeodomain is sufficient to enable naive pluripotency in Nanog–/– somatic cells. These functional studies, together with genome analyses, suggest that Nanog is a vertebrate innovation and that its reprogramming capacity resides within a unique DNA-binding domain that probably appeared at least 450 million years ago in a common ancestor of vertebrates.
