Naïve pluripotency is sustained by a self-reinforcing gene regulatory network (GRN) comprising core and naïve pluripotency-specific transcription factors (TFs). Upon exiting naïve pluripotency, embryonic stem cells (ESCs) transition through a formative post-implantation-like pluripotent state, where they acquire competence for lineage choice. However, the mechanisms underlying disengagement from the naïve GRN and initiation of the formative GRN are unclear. Here, we demonstrate that phosphorylated AKT acts as a gatekeeper that prevents nuclear localisation of FoxO TFs in naïve ESCs. PTEN-mediated reduction of AKT activity upon exit from naïve pluripotency allows nuclear entry of FoxO TFs, enforcing a cell fate transition by binding and activating formative pluripotency-specific enhancers. Indeed, FoxO TFs are necessary and sufficient for the activation of the formative pluripotency-specific GRN. Our work uncovers a pivotal role for FoxO TFs in establishing formative post-implantation pluripotency, a critical early embryonic cell fate transition.

初始多能性由自我强化基因调控网络 （GRN） 维持，该网络由核心和初始多能性特异性转录因子 （TF） 组成。在退出初始多能性后，胚胎干细胞 （ESC） 通过形成性植入后样多能状态过渡，在那里它们获得谱系选择的能力。然而，脱离初始 GRN 和形成性 GRN 启动的机制尚不清楚。在这里，我们证明了磷酸化的 AKT 充当守门人，可防止 FoxO TFs 在幼稚 ESC 中的核定位。PTEN 介导的 AKT 活性降低在脱离初始多能性后允许 FoxO TFs 进入核，通过结合和激活形成性多能性特异性增强子来强制细胞命运转变。事实上，FoxO TFs 对于形成性多能性特异性 GRN 的激活是必要且足够的。我们的工作揭示了 FoxO TFs 在建立形成性植入后多能性（一种关键的早期胚胎细胞命运转变）中的关键作用。