Nonlinear readout of spatial cues underlies robustness of asymmetric cell division

A key challenge in the development of an organism is to maintain robust phenotypic outcomes in the face of perturbation. Yet, how such robust outcomes are encoded by developmental networks remains poorly explored. Here we use the C. 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. Specifically, our data point towards an intrinsic 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. At the same time, we find that downstream pathways involved in cell size and fate asymmetry are similarly robust to dosage-dependent changes in the local concentrations of PAR proteins, implying non-trivial complexity in translating PAR signals into pathway outputs. We propose that "quantitative decoupling" of symmetry-breaking, polarity, and asymmetric division modules acts to suppress the accumulation of error as embryos move along this 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.