Encoding of temporal signals by the TGF-b 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 TGF-β pathway has the potential to behave as a morphogen: in vitro experiments have clearly established that it can dictate cell fate in a concentration dependent manner. How morphogens convey positional information in a developing embryo, where signal levels are changing 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-β signaling outcomes. The response to a TGF-β 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.
