Intermittent ERK oscillations downstream of FGF in mouse embryonic stem cells

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.