Under normal circumstances, mouse embryonic stem cells cannot persist without the cytokine leukaemia inhibitory factor, known more commonly as LIF. There are, however, at least two reported ways around this need: artificially activating the transcription factor Stat3 or overexpressing the transcription factor Nanog. Efforts to find a connection between these two proteins have been in vain. Now researchers led by Hitoshi Niwa of the RIKEN Center for Developmental Biology in Kobe, Japan show why: LIF is involved in two separate signaling pathways that both govern pluripotency.

First the researchers showed that mouse ES cells could be maintained without LIF if the expression of either of two other transcription factors, Klf4 or Tbx3 was kept active. Niwa's team made three transgenic lines of embryonic stem cells, each lacking a gene for a pluripotency factor, either Nanog, Klf4, or Tbx3. Next, they carefully assessed and correlated expression of other factors implicated in pluripotency including Oct3/4, Sox2, and MAPK.

Further work revealed the components of two parallel pathways: the Jak-Stat3, first activates Klf4 and then Sox2 but not Nanog. The PI3K-Akt pathway activates Tbx3 and then preferentially Nanog. Both of these, however, maintain Oct4 expression.

For scientists in the field, all of these transcription factors are very familiar names. This work, however, is the first to describe the hierarchy that functions to maintain self-renewal in mouse ES cells. The transcription factors working through Sox2 commit cells to pluripotency, and the others allow for what Niwa calls a "signal" integration" that depends on context. Identification of additional transcription factors in the commitment category will, Niwa believes, contribute to the efficient production of ES cells.