Research Highlights

Nature Reports Stem Cells
Published online: 14 February 2008 | doi:10.1038/stemcells.2008.33

Nanog's new trick

Asher Mullard¹

Nanog inhibits NFB signaling and cooperates with Stat3 to maintain pluripotency

Mouse embryonic stem (ES) cells need Nanog to stay as stem cells, but no one knows why. Reporting in Nature Cell Biology, Josema Torres, from the Wellcome Trust Centre, and Fiona Watt, from Wellcome Trust and Cancer Research UK, both in Cambridge, now link the transcription factor's function to two major signalling pathways: nuclear factor-B (NFB) and leukaemia inhibitory factor (LIF)/gp130 signalling.

To figure out how Nanog helps maintain pluripotency, the authors screened mouse embryonic stem (ES) cell lysates to identify proteins that interacted with Nanog. Among the hits were RelA, RelB and c-Rel, which are NFB-family transcription factors. In a separate experiment, overexpressing Nanog inhibited NFB-dependent transcription.

To determine the effect of NFB signalling on mouse ES cell pluripotency, the authors modulated NFB activity by overexpressing NFB activating or inhibiting proteins and evaluated differentiation by assessing morphology and measuring pluripotency markers. Activating NFB increased differentiation, whereas inhibiting NFB promoted pluripotency. Additionally, Nanog levels decreased during differentiation, whereas NFB activity and expression of NFB-regulated genes increased.

In a separate set of experiments, the authors examined the proposal that Nanog might maintain pluripotency by enhancing the activity of the transcription factor signal transducer and activator of transcription-3 (Stat3), which is activated by LIF. Indeed, Nanog overexpression in LIF-treated ES cells increased the activity of Stat3-dependent reporters. However, using immunoprecipitation techniques, the authors found that Stat3 and Nanog do not bind one another; rather, they bind the same regulatory regions of DNA.

These findings clarify how Nanog maintains pluripotency and establishes a new role for NFB signalling. Intriguingly, NFB signalling seems to have the opposite effect in human ES cells — it promotes pluripotency. However, as pluripotency in human ES cells depends on an interplay between the ES cells and the differentiated cells that they are cocultured with. The authors speculate that NFB signalling in differentiated cells might be indirectly promoting pluripotency in undifferentiated cells. Although further studies are needed to clarify how NFB functions in humans, the authors now plan to determine which genes are upregulated when Stat3 and Nanog function in synergy, which could help to define the ground state of pluripotency.

Author affiliation

1. Asher Mullard is Assistant Editor for Nature Reviews Molecular Cell Biology and Nature Reviews Microbiology