Several signalling pathways and transcription factors have been implicated in the maintenance of the self-renewal properties of mouse embryonic stem cells. Two studies (Cell Stem Cell 11, 477–490 2012; 491–504; 2012) report that two transcription factors of the pluripotency network critically act on one common target, the orphan nuclear hormone receptor Esrrb.

It is known that inhibition of glycogen synthase kinase 3 (GSK3) signalling, by stabilizing β-catenin, relieves Tcf3 repressor function to maintain self-renewal of mouse embryonic stem cells. However, the critical targets of Tcf3 in the process were unclear. Smith and colleagues carried out an analysis of Tcf3 binding sites and combined it with a survey of genes upregulated in the absence of Tcf3 to identify 9 transcription factors that could be direct targets of Tcf3. They then showed that only one of them, Esrrb, is necessary and sufficient for self-renewal downstream of GSK3 inhibition. Chambers and colleagues also identified Esrrb while searching for the targets of Nanog, a transcription factor that has been linked to the maintenance of pluripotency. They found that Nanog directly stimulates the expression of Esrrb, and that Esrrb expression is sufficient to restore the loss of self-renewal and reprogramming properties associated with loss of Nanog. Both studies also show that Esrrb is not required for self-renewal in the presence of the signalling molecule LIF (leukaemia inhibitory factor), suggesting that several pluripotency modules may be acting in parallel.