Quantitative guiding of developmental cell fate transitions using gene-free modelling

Abstract

During development, cells gradually assume specialized fates via changes of transcriptional dynamics in thousands of genes. Terminal cell identities are then stabilized through the convergence of gene regulatory network dynamics and the accumulation of epigenetic DNA modifications. “Gene-free” (or geometric) modeling approaches for cell fate acquisition, which abstract from the underlying gene regulatory landscape and reason in phenotypic space, have been remarkably successful in explaining terminal fate outcomes. However, their implications for cellular dynamics during fate acquisition processes have so far not been testedin vivo. To do so, here we combine gene-free mathematical modeling of cell fate acquisition duringC. elegansvulval development with temporally controlled perturbations ofin vivosignaling dynamics using temperature sensitive (ts) mutant alleles of the EGF/Ras/MAPK and Notch signaling pathways. We show that gene-free modeling can quantitatively predict non-intuitive fate outcomes in a variety of ts genetic backgrounds, including pathway epistasis effects. In addition, we use gene-free modeling to infer how cell fate transitions can be guided towards specific outcomes through timed pulses of signaling activity and verify these model predictions quantitatively with temporally controlled signaling perturbations via temperature shifts in ts backgrounds. Our results highlight the predictive power of gene-free models beyond terminal fate outcomes and illustrate a new approach to quantitatively guide cell fate acquisition in a developmental context.