Abstract
SummaryThe conserved polarity effector proteins PAR-3, PAR-6, CDC-42, and atypical protein kinase C (aPKC) form a core unit of the PAR protein network, which plays a central role in polarizing a broad range of animal cell types. To functionally polarize cells, these proteins must activate aPKC within a spatially defined membrane domain on one side of the cell in response to symmetry-breaking cues. Using the Caenorhabditis elegans zygote as a model, we find that the localization and activation of aPKC involve distinct, specialized aPKC-containing assemblies: a PAR-3-dependent assembly that responds to polarity cues and promotes efficient segregation of aPKC toward the anterior but holds aPKC in an inactive state, and a CDC-42-dependent assembly in which aPKC is active but poorly segregated. Cycling of aPKC between these distinct functional assemblies, which appears to depend on aPKC activity, effectively links cue-sensing and effector roles within the PAR network to ensure robust establishment of polarity.
Highlights
A crucial step in the polarization of metazoan cells is the localization of conserved sets of polarity effectors, known as the partitioning-defective or PAR proteins, to discrete membrane-associated cortical domains
We find that localized PKC-3 kinase activity is linked to dynamic cycling of PAR-6/PKC-3 between two functionally distinct aPAR assemblies: (1) a PAR-3-dependent assembly that is associated with clusters and efficiently responds to polarizing cues, but in which PKC-3 activity is inhibited, and (2) a more diffuse CDC-42-dependent assembly that is less able to respond to polarizing cues but contains active PKC-3 and is responsible for posterior PAR protein exclusion
Loss of asymmetry was quantified by the asymmetry index (ASI), which measures the asymmetry of a feature, e.g., PAR-2 membrane intensity, relative to wild-type on a scale from zero to 1 (Figure 1D and Movie S1)
Summary
A crucial step in the polarization of metazoan cells is the localization of conserved sets of polarity effectors, known as the partitioning-defective or PAR proteins, to discrete membrane-associated cortical domains. Regulation of PAR protein distribution is essential for the localized activation of signaling pathways that coordinate many aspects of embryonic development, including asymmetric cell division, epithelial organization, and embryo axis establishment (Goldstein and Macara, 2007; St Johnston and Ahringer, 2010). In Caenorhabditis elegans, PAR-3, PAR-6, CDC-42, and the aPKC ortholog, PKC-3, play an essential role in polarizing the one-cell embryo or zygote by defining an anterior domain and are referred to as anterior PARs or aPARs (Figures 1A–1C). APARs and pPARs define the anterior-posterior axis of the zygote and orchestrate an asymmetric division that restricts germline determinants to the posterior daughter cell (Beatty et al, 2010; Boyd et al, 1996; Etemad-Moghadam et al, 1995; Gotta et al, 2001; Guo and Kemphues, 1995; Hoege et al, 2010; Kay and Hunter, 2001; Kumfer et al, 2010; Tabuse et al, 1998; Watts et al, 1996)
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