Establishment of anterior-posterior polarity in the C. elegans zygote requires two different processes: mechanical activity of the actin-myosin cortex and biochemical activity of partitioning defective (PAR) proteins. Here, we have analyzed how PARs regulate the behavior of the cortical motor protein non-muscle myosin (NMY-2) to
complement recent efforts that investigate how PARs regulate the Rho GTPase CDC-42, which in turn regulates the actin-myosin cortex. We found that PAR-3 and PAR-6 concentrate CDC-42-dependent NMY-2 in the anterior cortex, while PAR-2 inhibits CDC-42-dependent NMY-2 in the posterior by inhibiting PAR-3 and PAR-6. Additionally, we found that PAR-1 and PAR-3 are necessary for inhibiting movement of NMY-2 across the cortex. PAR-1 protects NMY-2 from being moved across the cortex by forces likely originating in the cytoplasm. Meanwhile, PAR-3 stabilizes NMY-2 against PAR-2 and PAR-6 dynamics on the cortex. We found that PAR signaling fulfills two roles: localizing NMY-2 to the anterior cortex and preventing displacement of the polarized cortical actin-myosin network.
We then have extended the themes of this work to hypothesize how crosstalk between PAR proteins and Rho GTPases may be at work in other biological contexts, and we propose how improved mathematical modeling will increase our understanding of this PAR/Rho GTPase interaction. In C. elegans, PAR-6 may directly interact with CDC-42 and positively regulate its activity. PAR proteins are also necessary for proper localization of the CDC-42 regulating protein CHIN-1. In motile cells, PAR proteins provide a second input into the Rho GTPase pathway by upregulating Rac1 and downregulating RhoA. We propose that incorporating these and other new research into
models of cell polarization will greatly increase the power of those models.
In summary, the work presented in this dissertation increases our understanding of the several ways that PAR signaling can influence Rho GTPase in the context of myosin dynamics. We have applied this new understanding and other work in the field to characterization of the C. elegans zygote and to the improvement of mathematical models of cell polarization.