Abstract
The evolutionarily conserved Par3/Par6/aPKC complex regulates the polarity establishment of diverse cell types and distinct polarity-driven functions. However, how the Par complex is concentrated beneath the membrane to initiate cell polarization remains unclear. Here we show that the Par complex exhibits cell cycle-dependent condensation in Drosophila neuroblasts, driven by liquid–liquid phase separation. The open conformation of Par3 undergoes autonomous phase separation likely due to its NTD-mediated oligomerization. Par6, via C-terminal tail binding to Par3 PDZ3, can be enriched to Par3 condensates and in return dramatically promote Par3 phase separation. aPKC can also be concentrated to the Par3N/Par6 condensates as a client. Interestingly, activated aPKC can disperse the Par3/Par6 condensates via phosphorylation of Par3. Perturbations of Par3/Par6 phase separation impair the establishment of apical–basal polarity during neuroblast asymmetric divisions and lead to defective lineage development. We propose that phase separation may be a common mechanism for localized cortical condensation of cell polarity complexes.
Highlights
The evolutionarily conserved Par3/Par6/aPKC complex regulates the polarity establishment of diverse cell types and distinct polarity-driven functions
Careful analyses of microscopy images of dividing NBs showed that endogenous Baz, Par[6], and aPKC displayed cell cycle-dependent puncta formation on the apical cortex (Fig. 1), just like their C. elegans counterparts during embryonic polarization[30,31]
We investigated the specific role of the direct Par3N–Par6β interaction or oligomerization of each protein in promoting Par3N/ Par6β phase separation, at a concentration relatively low (~3 μM) but with nearly saturating liquid–liquid phase separation (LLPS) capacity (Fig. 3d)
Summary
The evolutionarily conserved Par3/Par6/aPKC complex regulates the polarity establishment of diverse cell types and distinct polarity-driven functions. How the Par complex is concentrated beneath the membrane to initiate cell polarization remains unclear. We show that the Par complex exhibits cell cycle-dependent condensation in Drosophila neuroblasts, driven by liquid–liquid phase separation. Perturbations of Par3/Par[6] phase separation impair the establishment of apical–basal polarity during neuroblast asymmetric divisions and lead to defective lineage development. We propose that phase separation may be a common mechanism for localized cortical condensation of cell polarity complexes. The Par complex proteins, including Par[3] (Bazooka, Baz in Drosophila), Par[6], and atypical protein kinase (aPKC), are multidomain proteins capable of binding to each other and a diverse range of other cell polarity-regulating proteins[13]. A recent study showed that both PDZ1 and PDZ3 of Baz weakly bind to a PDZ-
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