The protein Nanog, long considered essential to maintaining pluripotency and promoting differentiation in embryonic stem cells, may play a lesser role in those processes, according to a study published this week in Nature.

"The previous paradigm was that Nanog was infinitely coupled to differentiation," Ian Chambers of the University of Edinburgh, lead author of the study, told The Scientist. This new work has shown, Chambers continued, that embryonic stem cells that express no Nanog can still self-renew and differentiate.

While previous research has shown that early-stage embryos can't survive without Nanog, the level of protein expression required was unknown. Chambers' group examined expression levels of Nanog in the nuclei of undifferentiated mouse embryonic stem cells, and found that the expression, in fact, fluctuates in undifferentiated stem cells. Further, they showed that self-renewal was not tied to Nanog expression, since it is maintained even in Nanog knock-out cells, though at a lesser rate. However, Nanog is still essential for the formation of germ cells, the study showed.

Researchers previously thought that Nanog controlled self-renewal much like an on-and-off switch, Chambers said, but this new view characterizes Nanog as more of a dimmer switch; when Nanog expression is high, self-renewal is high. Some other protein must be functioning as the on-and-off switch that more strongly regulates self-renewal, he added.

"This will help in improving our understanding of the likely role of Nanog during embryogenesis," Angie Rizzino of the University of Nebraska Medical Center, who was not involved in the study, told The Scientist. "But my suspicion is that that's not the whole story." In particular, why Nanog is so important for early stage embryos but nonessential in self-renewal and differentiation is still murky.

In a recent paper on reprogramming human somatic cells into embryonic stem cell-like cells by James Thomson's group at the University of Wisconsin, Madison, Nanog appeared to increase clone survival, but was not necessary for reprogramming the cells. Chambers' group speculates that Nanog stabilizes embryonic stem cells by inhibiting the expression of other genes.