Encoding of Temporal Signals by the TGF-β Pathway and Implications for Embryonic Patterning

Genetics and biochemistry have defined the components and wiring of the signaling pathways that pattern the embryo. Among them, the transforming growth factor beta (TGF-beta) pathway has the potential to behave as a morphogen: in vitro experiments established that it can dictate cell fate in a concentration-dependent manner. How morphogens convey positional information in a developing embryo, when signal levels change with time, is less understood. Using integrated microfluidic cell culture and time-lapse microscopy, we demonstrate here that the speed of ligand presentation has a key and previously unexpected influence on TGF-beta signaling outcomes. The response to a TGF-beta concentration step is transient and adaptive: slowly increasing the ligand concentration diminishes the response, and well-spaced pulses of ligand combine additively, resulting in greater pathway output than with constant stimulation. Our results suggest that in an embryonic context, the speed of change of ligand concentration is an instructive signal for patterning.