Quantitative guiding of developmental cell fate transitions using a dynamical landscape model

During development, cells gradually assume specialized fates via changes of transcriptional dynamics in thousands of genes. Landscape modeling approaches, which abstract from the underlying gene regulatory networks and reason in a low-dimensional phenotypic space, have been remarkably successful in explaining terminal fate outcomes. However, their implications for the dynamics of fate acquisition have so far not been tested in vivo. Here we combine a landscape model for C. elegans vulval fate patterning with temporally controlled perturbations of EGF and Notch signaling in vivo using temperature-sensitive mutant alleles. We show that this approach quantitatively predicts non-intuitive fate outcomes and pathway epistasis effects. We further infer how cell fate transitions can be guided towards specific outcomes through timed pulses of signaling activity and verify these model predictions experimentally. Our results highlight the predictive power of landscape models and illustrate a new approach to quantitatively guide cell fate acquisition in a developmental context.