Combinatorial interpretation of BMP and WNT allows BMP to act as a morphogen in time but not in concentration

Secreted morphogen signals play a key role in the determination of cell fates during embryonic development. BMP signaling is essential for mammalian gastrulation, as it initiates a cascade of signals that controls the self-organized patterning of the three germ layers. Although morphogen signals are typically thought to induce cell fates in a concentration-dependent manner, development is a highly dynamic process, so it is crucial to understand how time-dependent signaling affects cellular differentiation. Here we show that varying the duration of BMP signaling in human pluripotent stem cells (hPSCs) leads to either cells remaining pluripotent, or differentiating to mesodermal or extraembryonic states, while varying the concentration does not cause efficient mesodermal differentiation at any dose. Thus, there is a morphogen effect in time but not in concentration, and an appropriately timed pulse of BMP induces hPSCs to a mesodermal fate more efficiently than sustained signaling at any concentration. Using live cell imaging of signaling and cell fate reporters together with a simple mathematical model, we show that this effect is due to a combinatorial interpretation of the applied BMP signal and induced endogenous WNT signaling. Our findings have implications for how signaling pathways control the landscape of early human development.