Bistable Cellular Fate Commitment in Developmen*

The precise adoption of cellular fates is a central question in developmental biology. Cells are believed to adopt their unique gene expression profiles through a series of decisions among branching paths, represented by "Waddington's landscape". Positive autoregulation has been proposed as a mechanism for cells to adopt binary fates during embryonic development through bistability. However, unless their parameters are quantitatively determined, it is unclear if positive autoregulatory modules found within developmental gene regulatory networks are actually bistable. We combined in vivo live imaging with mathematical modeling to study the fruit fly pair-rule gene fushi tarazu (ftz), which activates its own expression in a positive feedback loop. We developed a dynamical systems model of ftz autoregulation and determined its parameters through independent experiments, leading to the parameter-free prediction of single-cell expression dynamics. Using this model, we discovered that ftz regulation is indeed bistable and that cells commit to their Ftz expression fate quickly, within 35 minutes of exposure to transient input signals. Our work confirms the widely held hypothesis that autoregulation can establish developmental fates through bistability and, most importantly, provides a framework for the quantitative dissection of cellular decision-making based on a dialogue between theory and experiment.