Reconciling the different roles of Gsk3β in naive and primed pluripotent stem cells

Signaling pathways orchestrated by PI3K/Akt, Raf/Mek/Erk and Wnt/beta-catenin are known to play key roles in the self-renewal and differentiation of pluripotent stem cells. The serine/threonine protein kinase Gsk3 beta has roles in all three pathways, making its exact function difficult to decipher. Consequently, conflicting reports have implicated Gsk3 beta in promoting self-renewal, while others suggest that it performs roles in the activation of differentiation pathways. Different thresholds of Gsk3 beta activity also have different biological effects on pluripotent cells, making this situation even more complex. Here, we describe a further level of complexity that is most apparent when comparing naive murine and primed human pluripotent stem cells. In naive cells, Gsk3 beta activity is restrained by PI3K/Akt, but when released from inhibitory signals it antagonizes self-renewal pathways by targeting pluripotency factors such as Myc and Nanog. This situation also applies in primed cells, but, in addition, a separate pool of Gsk3 beta is required to suppress canonical Wnt signaling. These observations suggest that different Gsk3 beta-protein complexes shift the balance between naive and primed pluripotent cells and identify fundamental differences in their cell signaling. Altogether, these findings have important implications for the mechanisms underpinning the establishment of different pluripotent cell states and for the control of self-renewal and differentiation.