期刊
FASEB JOURNAL
卷 21, 期 9, 页码 2020-2032出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.06-7852com
关键词
positive feedback; cell signaling; Jak-STAT; threshold; systems biology
Stem cells convert graded stimuli into all-or-nothing cell-fate responses. We investigated how embryonic stem cells (ESCs) convert leukemia inhibitory factor (LIF) concentration into an all-or-nothing cell-fate decision (self-renewal). Using a combined experimental/computational approach we demonstrate unexpected switch-like (on/off) signaling in response to LIF. This behavior emerges over time due to a positive feedback loop controlling transcriptional expression of LIF signaling pathway components. The autoregulatory loop maintains robust pathway responsiveness (on) at sufficient concentrations of exogenous LIF, while autocrine signaling and low concentrations of exogenous LIF cause ESCs to adopt the weakly responsive (off) state of differentiated cells. We demonstrate that loss of ligand responsiveness is reversible and precedes loss of the ESC transcription factors Oct4 and Nanog, suggesting an early step in the hierarchical control of differentiation. While endogenously produced ligands were insufficient to sustain the on state, they buffer it, influencing the timing of differentiation. These results demonstrate a novel switch-like behavior, which establishes the LIF threshold for ESC self-renewal.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据