Caenorhabditis elegans par genes.

What are they? Six par genes (par-1 through par-6) have been identified in Caenorhabditis elegans. Loss-of-function mutations in any par locus results in loss of anterior–posterior (AP) asymmetries during the first two embryonic cell divisions. This results in a failure to restrict developmental regulators to specific embryonic cells, mitotic spindle orientation defects and abnormal cell fate patterning. In sum, the par genes appear responsible for establishing asymmetries that define the AP body axis in C. elegans.What about the PAR proteins? PAR-1 and PAR-4 are putative Ser/Thr kinases; PAR-2 is a ring finger protein; PAR-3 and PAR-6 are PDZ domain proteins; and PAR-5 is a 14-3-3 protein. Several PAR proteins are polarized in distribution. In a one-cell embryo, PAR-3 and PAR-6, together with PKC-3 (an aPKC homologue), form a complex throughout the anterior cytoplasmic cortex. PAR-1 and PAR-2 are enriched in the posterior cortex. These two domains of cortical PAR protein abut roughly mid-way along the AP axis.How is PAR asymmetry set up? The sperm-donated pronucleus, with an associated centrosome, marks the posterior of the embryo. This cue may involve sperm aster microtubules contacting the microfilament-rich cortex, or other centrosome-associated functions. The microfilament cytoskeleton and myosin motor activity are then required to establish asymmetries, including the polarized distribution of PAR proteins.How is it maintained? The PAR proteins interact. In par-2 mutants, the PAR-3/PAR-6/PKC-3 complex extends to the posterior, and in par-3, par-6 and pkc-3 mutants, PAR-2 and PAR-1 extend to the anterior. At the 2-cell stage, in the posterior cell called P1, PAR asymmetry is reiterated. A recent study suggests that the P1 mitotic spindle is polarized, maintaining cortical polarity after the spindle rotates from a transverse to a longitudinal orientation (see Figure 1Figure 1). This rotation is thought to result from capture of one spindle pole by a discrete cortical site, and may be coordinated with spindle polarization. In the absence of a putative RNA binding protein called SPN-4, the P1 spindle fails to rotate but still becomes polarized. By contrast, the P1 spindle fails to rotate or become polarized in the absence of heterotrimeric G proteins. Thus G proteins may be required for polarization of the mitotic spindle, while SPN-4 appears to regulate rotation (see Figure 1Figure 1).Figure 1In the zygote (P0) the sperm specifies the posterior pole and establishes PAR domains. At the 2-cell stage P1 reiterates a similar distribution of PAR proteins. In P1 the mitotic spindle rotates (black arrows), following capture of one pole by a discrete cortical site. This rotation may be coordinated with polarization of the spindle (purple arrow).View Large Image | View Hi-Res Image | Download PowerPoint SlideHow does PAR asymmetry affect cell fate? The PAR proteins control asymmetry in the first embryonic cell division, differentially distributing maternally expressed regulatory proteins to early embryonic cells. These different combinations of maternal factors activate distinct patterns of gene transcription. Several CCCH finger proteins (MEX-1, MEX-5, MEX-6, PIE-1, POS-1) and two putative RNA binding proteins (MEX-3, SPN-4) may mediate the transfer of cortical PAR polarity into a differential distribution of cytoplasmic regulatory proteins, through a combination of changes in protein stability and localized mRNA translation.Are PAR proteins conserved? The PAR-3/PAR-6/PKC-3 complex is conserved throughout evolution. In mammalian epithelia, the orthologues ASIP (PAR-3), PAR-6 and aPKC (PKC-3) localize to junctional complexes, and the PAR-1 orthologue, MARK, to the basolateral cortex. In Drosophila neuroblasts, Bazooka (PAR-3), DmPAR-6 and DaPKC form a cortical crescent required for asymmetric division. Drosophila neuroblasts resemble P1 in C. elegans in that the position of the Bazooka/DmPAR-6/DaPKC crescent can be specified late during cell division by the mitotic spindle in some mutants, a process called ‘telophase rescue’. This rescue does not occur in the absence of heterotrimeric G proteins, suggesting that their role in polarization of mitotic spindles may be widely conserved.