Abstract：
Naïve epiblast cells in the embryo and pluripotent stem cells in vitro undergo developmental progression to a formative state competent for lineage specification. During this transition, transcription factors and chromatin are rewired to encode new functional features. Here, we examine the role of mitogen-activated protein kinase (ERK1/2) signalling in pluripotent state transition. We show that a primary consequence of ERK activation in mouse embryonic stem cells is elimination of Nanog, which precipitates breakdown of the naïve state gene regulatory network. Variability in pERK dynamics results in heterogeneous loss of Nanog and metachronous state transition. Knockdown of Nanog allows exit without ERK activation. However, transition to formative pluripotency does not proceed and cells collapse to an indeterminate identity. This outcome is due to failure to maintain expression of the central pluripotency factor Oct4. Thus, during formative transition ERK signalling both dismantles the naïve state and preserves pluripotency. These results illustrate how a single signalling pathway can both initiate and secure transition between cell states.
摘要：
胚胎中的原始表皮细胞和体外的多能干细胞经历发育进展至具有谱系规格能力的形成状态。在这个转变过程中,转录因子和染色质被重新连接以编码新的功能特征。这里,我们研究了丝裂原活化蛋白激酶(ERK1/2)信号在多能状态转换中的作用.我们表明，小鼠胚胎干细胞中ERK激活的主要结果是消除Nanog，这促使幼稚状态的基因调控网络崩溃。pERK动力学的变异性导致Nanog的异质损失和异时态转变。Nanog的击倒允许在没有ERK激活的情况下退出。然而,向形成性多能性的转变不会进行，细胞崩溃到不确定的身份。该结果是由于未能维持中心多能性因子0ct4的表达。因此，在形成性过渡过程中，ERK信号既可以消除幼稚状态，又可以保留多能性。这些结果说明了单个信号通路如何启动和确保细胞状态之间的转换。
