PAR-3 Oligomerization May Provide an Actin-Independent Mechanism to Maintain Distinct Par Protein Domains in the Early Caenorhabditis elegans Embryo

Abstract

Par proteins establish discrete intracellular spatial domains to polarize many different cell types. In the single-cell embryo of the nematode worm Caenorhabditis elegans, the segregation of Par proteins is crucial for proper division and cell fate specification. Actomyosin-based cortical flows drive the initial formation of anterior and posterior Par domains, but cortical actin is not required for the maintenance of these domains. Here we develop a model of interactions between the Par proteins that includes both mutual inhibition and PAR-3 oligomerization. We show that this model gives rise to a bistable switch mechanism, allowing the Par proteins to occupy distinct anterior and posterior domains seen in the early C. elegans embryo, independent of dynamics or asymmetries in the actin cortex. The model predicts a sharp loss of cortical Par protein asymmetries during gradual depletion of the Par protein PAR-6, and we confirm this prediction experimentally. Together, these results suggest both mutual inhibition and PAR-3 oligomerization are sufficient to maintain distinct Par protein domains in the early C. elegans embryo.

PAR-2, LGL-1 and the CDC-42 GAP CHIN-1 act in distinct pathways to maintain polarity in the C. elegans embryo

“…We found that reducing the levels of active CDC-42 via cgef-1 mutation during polarity maintenance results in a substantial decrease in cortical myosin, even in par-6 mutants, suggesting that CDC-42 has two separable functions in polarity maintenance. In contrast to the role of CDC-42 in binding to PAR-6, the role of CDC-42 in cortical myosin regulation via MRCK-1 during polarity maintenance appears to be dispensable, consistent with the observation that the actomyosin cytoskeleton is not required for the maintenance of distinct cortical domains (Dawes and Munro, 2011;Goehring et al, 2011a;Goehring et al, 2011b).…”

“…We propose that the two effects exert unequal influence on polarity maintenance and that suppression of PAR-2 by CGEF-1 occurs because reduced active CDC-42 will restore the balance between the antagonistic forces of the anterior and posterior domains. Lowering MRCK-1 levels lowers the levels of cortical myosin in the anterior (Kumfer et al, 2010) but appears to have no effect on the size of the PAR-6 domain, consistent with the observation that the actomyosin cytoskeleton is not required for the maintenance of distinct cortical domains (Dawes and Munro, 2011;Goehring et al, 2011a;Goehring et al, 2011b). As mentioned above, however, the ability of mrck-1(RNAi) to partially block LGL-1 overexpression rescue of par-2 argues that MRCK-1 normally contributes to maintaining the anterior cortical domain, although this contribution is nonessential in a normal genetic background.…”

“…Taken together, our results suggest that LGL-1 negatively regulates the overall amount of PAR-6 in the early embryo and thus may buffer against expansion of the anterior cortical domain (Dawes and Munro, 2011). Although the molecular mechanism by which LGL-1 acts remains elusive, we suggest that polarity maintenance in the one-cell C. elegans embryo may represent another instance where LGL functions as a molecular buffer, but in a method that is distinct from that reported for the peripheral nervous system of Drosophila (Wirtz-Peitz et al, 2008).…”

Protein abundance may regulate sensitivity to external cues in polarized cells

“…We focus on how protein abundance influences the behaviour of both the deterministic and stochastic versions of the model. In Dawes & Munro (2011), it was found that bistable behaviour in the temporal model of Par protein led to the existence of complementary domains in the corresponding spatio-temporal model. Here, we find that the corresponding temporal stochastic model permits switching behaviour (the model solution 'jumps' between steady states) for lower protein abundances, whereas for higher protein abundances the stochastic and deterministic models are in good agreement (the model solution evolves to one of two steady states).…”

“…A key player in this process is the Par protein family whose asymmetric localization to anterior and posterior parts of the cell is crucial for proper division and cell fate specification. In this paper, we explore a stochastic analogue of the temporal model of Par protein interactions first developed in Dawes & Munro (Dawes and Munro 2011 Biophys. J.…”