Abstract
SummaryHow do cells polarize at the correct time and in response to the correct cues? In the C. elegans zygote, the timing and geometry of polarization rely on a single dominant cue—the sperm centrosome—that matures at the end of meiosis and specifies the nascent posterior. Polarization requires that the conserved PAR proteins, which specify polarity in the zygote, be poised to respond to the centrosome. Yet, how and when PAR proteins achieve this unpolarized, but responsive, state is unknown. We show that oocyte maturation initiates a fertilization-independent PAR activation program. PAR proteins are initially not competent to polarize but gradually acquire this ability following oocyte maturation. Surprisingly, this program allows symmetry breaking even in unfertilized oocytes lacking centrosomes. Thus, if PAR proteins can respond to multiple polarizing cues, how is specificity for the centrosome achieved? Specificity is enforced by Polo-like and Aurora kinases (PLK-1 and AIR-1 in C. elegans), which impose a delay in the activation of the PAR network so that it coincides with maturation of the centrosome cue. This delay suppresses polarization by non-centrosomal cues, which can otherwise trigger premature polarization and multiple or reversed polarity domains. Taken together, these findings identify a regulatory program that enforces proper polarization by synchronizing PAR network activation with cell cycle progression, thereby ensuring that PAR proteins respond specifically to the correct cue. Temporal control of polarity network activity is likely to be a common strategy to ensure robust, dynamic, and specific polarization in response to developmentally deployed cues.
Highlights
Functional polarization of cells underlies a diversity of morphological events, including the generation of complex cell shapes, establishment of tissue architecture, cell migration, and the generation of cell diversity through asymmetric cell division
Stereotyped Reconfiguration of the PAR Network Precedes Symmetry Breaking Despite extensive characterization of the process of symmetry breaking of the PAR network in the C. elegans zygote, little attention has been paid to the behavior of the PAR network prior to symmetry breaking
To quantitatively assess changes in PAR protein localization in live animals during this period, we developed an imaging pipeline that combined in utero imaging to establish timelines of key events relative to ovulation, with imaging of dissected oocytes and zygotes ex utero to quantify changes in localization over time (Figure 1B)
Summary
Functional polarization of cells underlies a diversity of morphological events, including the generation of complex cell shapes, establishment of tissue architecture, cell migration, and the generation of cell diversity through asymmetric cell division. A key requirement for polarization is the ability of cells to break symmetry, resulting in a single, properly oriented axis of symmetry. PAR polarity is required for the asymmetric division of the zygote and segregation of germline determinants [1]. Polarity emerges through selforganization of two antagonistic sets of PAR proteins on the plasma membrane into complementary domains that define the anterior-posterior axis [2, 3]. The anterior aPARs (PAR-3, PAR-6, PKC-3, and CDC-42) localize to the anterior cell pole, while the posterior pPARs (PAR-1, PAR-2, LGL-1, and CHIN-1) localize to the posterior pole. Their segregation within opposing domains is maintained through mutual antagonism. The kinase PKC-3 phosphorylates pPARs to displace them from the anterior cortex, while pPARs limit invasion of the posterior cortex by aPARs [4,5,6] (Figure 1A)
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