Quantitative perturbation-phenotype maps reveal nonlinear responses underlying robustness of PAR-dependent asymmetric cell division.

Abstract

A key challenge in the development of an organism is to maintain robust phenotypic outcomes in the face of perturbation. Yet, it is often unclear how such robust outcomes are encoded by developmental networks. Here, we use the Caenorhabditis elegans zygote as a model to understand sources of developmental robustness during PAR polarity-dependent asymmetric cell division. By quantitatively linking alterations in protein dosage to phenotype in individual embryos, we show that spatial information in the zygote is read out in a highly nonlinear fashion and, as a result, phenotypes are highly canalized against substantial variation in input signals. Our data point towards robustness of the conserved PAR polarity network that renders polarity axis specification resistant to variations in both the strength of upstream symmetry-breaking cues and PAR protein dosage. Analogously, downstream pathways involved in cell size and fate asymmetry are robust to dosage-dependent changes in the local concentrations of PAR proteins, implying nontrivial complexity in translating PAR concentration profiles into pathway outputs. We propose that these nonlinear signal-response dynamics between symmetry-breaking, PAR polarity, and asymmetric division modules effectively insulate each individual module from variation arising in others. This decoupling helps maintain the embryo along the correct developmental trajectory, thereby ensuring that asymmetric division is robust to perturbation. Such modular organization of developmental networks is likely to be a general mechanism to achieve robust developmental outcomes.