Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany.
Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Polo Científico Tecnológico, Godoy Cruz 2390, C1425FQD Buenos Aires, Argentina.
Development. 2022 Feb 15;149(4). doi: 10.1242/dev.199710. Epub 2022 Feb 17.
Signal transduction networks generate characteristic dynamic activities to process extracellular signals and guide cell fate decisions such as to divide or differentiate. The differentiation of pluripotent cells is controlled by FGF/ERK signaling. However, only a few studies have addressed the dynamic activity of the FGF/ERK signaling network in pluripotent cells at high time resolution. Here, we use live cell sensors in wild-type and Fgf4-mutant mouse embryonic stem cells to measure dynamic ERK activity in single cells, for defined ligand concentrations and differentiation states. These sensors reveal pulses of ERK activity. Pulsing patterns are heterogeneous between individual cells. Consecutive pulse sequences occur more frequently than expected from simple stochastic models. Sequences become more prevalent with higher ligand concentration, but are rarer in more differentiated cells. Our results suggest that FGF/ERK signaling operates in the vicinity of a transition point between oscillatory and non-oscillatory dynamics in embryonic stem cells. The resulting heterogeneous dynamic signaling activities add a new dimension to cellular heterogeneity that may be linked to divergent fate decisions in stem cell cultures.
信号转导网络产生特征性的动态活动，以处理细胞外信号并指导细胞命运决定，例如分裂或分化。多能细胞的分化受 FGF/ERK 信号的控制。然而，只有少数研究在高时间分辨率下研究了多能细胞中 FGF/ERK 信号网络的动态活性。在这里，我们使用野生型和 Fgf4 突变型小鼠胚胎干细胞中的活细胞传感器，以测量在单个细胞中针对特定配体浓度和分化状态的动态 ERK 活性。这些传感器揭示了 ERK 活性的脉冲。脉冲模式在单个细胞之间存在异质性。连续的脉冲序列比简单的随机模型所预期的更为频繁。随着配体浓度的增加，序列变得更为普遍，但在分化程度较高的细胞中则更为罕见。我们的结果表明，FGF/ERK 信号在胚胎干细胞中在振荡和非振荡动力学之间的转换点附近起作用。由此产生的异质动态信号活性为细胞异质性增加了一个新的维度，这可能与干细胞培养中不同的命运决定有关。
