Edwin M Munro et al. (2005) International Worm Meeting "Cortical mechanics meet regulatory biochemistry: modeling cell polarization in the C. elegans embryo"

Eliana Hechter, Edwin M Munro

[International Worm Meeting, 2005]

Polarization of the C. elegans zygote involves a complex network of interactions among PAR proteins and the cortical actomyosin cytoskeleton. Many of the key players are now known; their interactions are being rapidly characterized, and the outlines of a polarization mechanism have begun to emerge. But the complexity and distributed nature of these interactions makes it difficult to move beyond the outline to a deeper understanding of polarization. To address this issue, we have developed a computational model that integrates cytoskeletal mechanics and regulatory biochemistry to predict observed polarization dynamics from known interactions among PAR proteins and components of the actomyosin cytoskeleton. Here, we focus on local actomyosin dynamics and mechanisms that govern the initiation and extent of cortical flow and PAR protein movement during polarization, highlighting key insights, experimental predictions and confirmations: The model predicts that local actomyosin dynamics (the cyclic formation and disappearance of actomyosin foci) observed during polarization in living embryos emerge as a robust consequence of the local mechanochemistry of cross-linked actomyosin networks. Quantitative tunings of model parameters that govern F-actin assembly/disassembly, cross-link formation and myosin activity predict a range of contractility/cortical flow phenotypes that encompass those seen during genetic or pharmacological perturbations of polarization, including those caused by PAR mutants. We have confirmed some of these predictions experimentally. For quantitative parameter tunings that produce normally observed local actomyosin dynamics, the model predicts that interactions among anterior and posterior PAR proteins, and between PAR proteins and actomyosin, are required to convert a transient local weakening of the cortex (to mimic the sperm cue) into sustained cortical flow and polarization. Finally, analysis of the model reveals an unanticipated mechanism that could limit the extent of cortical flow as seen during normal polarization and thus determine the size of the anterior PAR domain. This mechanism works only for parameter tunings that support local contractile instabilities and actomyosin focus formation. As predicted, defeating this contractile instability experimentally (without abolishing contractility) causes an acute anterior shift of the anterior PAR domain. We are now using this model as a sophisticated working hypothesis to guide further experimental analysis of the polarization mechanism.