The C. elegans homolog of Drosophila Lethal giant larvae functions redundantly with PAR-2 to maintain polarity in the early embryo

Department of Molecular Biology and Genetics, Cornell University, 433 Biotechnology Building, Ithaca, NY 14850, USA.
Development (Impact Factor: 6.46). 11/2010; 137(23):3995-4004. DOI: 10.1242/dev.056028
Source: PubMed


Polarity is essential for generating cell diversity. The one-cell C. elegans embryo serves as a model for studying the establishment and maintenance of polarity. In the early embryo, a myosin II-dependent contraction of the cortical meshwork asymmetrically distributes the highly conserved PDZ proteins PAR-3 and PAR-6, as well as an atypical protein kinase C (PKC-3), to the anterior. The RING-finger protein PAR-2 becomes enriched on the posterior cortex and prevents these three proteins from returning to the posterior. In addition to the PAR proteins, other proteins are required for polarity in many metazoans. One example is the conserved Drosophila tumor-suppressor protein Lethal giant larvae (Lgl). In Drosophila and mammals, Lgl contributes to the maintenance of cell polarity and plays a role in asymmetric cell division. We have found that the C. elegans homolog of Lgl, LGL-1, has a role in polarity but is not essential. It localizes asymmetrically to the posterior of the early embryo in a PKC-3-dependent manner, and functions redundantly with PAR-2 to maintain polarity. Furthermore, overexpression of LGL-1 is sufficient to rescue loss of PAR-2 function. LGL-1 negatively regulates the accumulation of myosin (NMY-2) on the posterior cortex, representing a possible mechanism by which LGL-1 might contribute to polarity maintenance.

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Available from: Alexander Beatty, Nov 19, 2015
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    • "Current models propose a key role for PAR-2 in promoting local dissociation of PAR-6/PKC-3, which can be fulfilled in par-2 mutants by overexpressing LGL-1 (Beatty et al., 2010; Hoege et al., 2010). PAR-2 (and possibly LGL-1) is also required to prevent posterior directed flows that could redistribute PAR-6/ PKC-3 during early maintenance (Munro et al., 2004; Beatty et al., 2010), but the relative importance of dissociation and flow for maintaining PAR-6/PKC-3 asymmetries has not been determined. "
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    ABSTRACT: Dynamic maintenance of cell polarity is essential for development and physiology. Here we combine experiments and modeling to elucidate mechanisms that maintain cortical polarity in the C. elegans zygote. We show that polarity is dynamically stabilized by two coupled cross-inhibitory feedback loops: one involves the oligomeric scaffold PAR-3 and the kinase PAR-1, and the other involves CDC-42 and its putative GAP CHIN-1. PAR-3 and CDC-42 are both required locally to recruit PAR-6/PKC-3, which inhibits PAR-1 (shown previously) and inhibits local growth/accumulation of CHIN-1 clusters. Conversely, PAR-1 inhibits local accumulation of PAR-3 oligomers, while CHIN-1 inhibits CDC-42 (shown previously), such that either PAR-1 or CHIN-1 can prevent recruitment of PAR-6/PKC-3, but loss of both causes complete loss of polarity. Ultrasensitive dependence of CHIN-1 cluster growth on PAR-6/PKC-3 endows this core circuit with bistable dynamics, while transport of CHIN-1 clusters by cortical flow can stabilize the AP boundary against diffusive spread of PAR-6/PKC-3.
    Developmental Cell 10/2015; 35(1):131–142. DOI:10.1016/j.devcel.2015.09.006 · 9.71 Impact Factor
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    • "That is, variation at these loci must influence a very restricted suite of developmental events, since only specific perturbations uncover evidence of their phenotypic effects. For those associated with polarization of the zygote, this may be explained by the high degree of redundancy observed in the process (Beatty et al., 2010; Fievet et al., 2013; Motegi and Seydoux, 2013), as redundancy allows shared function of some factors and specificity of others. Exceptions to the overall trend of low correlation between gene perturbations are discussed below, in the context of genome-wide associations. "
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    ABSTRACT: Embryogenesis is an essential and stereotypic process that nevertheless evolves among species. Its essentiality may favor the accumulation of cryptic genetic variation (CGV) that has no effect in the wild-type but that enhances or suppresses the effects of rare disruptions to gene function. Here, we adapted a classical modifier screen to interrogate the alleles segregating in natural populations of C. elegans: we induced gene knockdowns and used quantitative genetic methodology to examine how segregating variants modify the penetrance of embryonic lethality. Each perturbation revealed CGV, indicating that wild-type genomes harbor myriad genetic modifiers that may have little effect individually but which in aggregate can dramatically influence penetrance. Phenotypes were mediated by many modifiers, indicating high polygenicity, but the alleles tend to act very specifically, indicating low pleiotropy. Our findings demonstrate the extent of conditional functionality in complex trait architecture.
    eLife Sciences 08/2015; 4. DOI:10.7554/eLife.09178 · 9.32 Impact Factor
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    • "lgl-1(À) mutants upregulate PAR-6 (Beatty et al., 2013), suggesting an aPAR/pPAR imbalance. Conversely, overexpression of LGL-1 can rescue severe loss of PAR-2, indicating that LGL-1 can function for PAR-2 (Beatty et al., 2010; Hoege et al., 2010). It remains unknown how PAR protein levels are tightly controlled to achieve the reproducible domain sizes observed in wild-type embryos. "
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    ABSTRACT: Cell polarity in one-cell C. elegans embryos guides asymmetric cell division and cell-fate specification. Shortly after fertilization, embryos establish two antagonistic cortical domains of PAR proteins. Here, we find that the conserved polarity factor PAR-5 regulates PAR domain size in a dose-dependent manner. Using quantitative imaging and controlled genetic manipulation, we find that PAR-5 protein levels reflect the cumulative output of three mRNA isoforms with different translational efficiencies mediated by their 3' UTRs. 3' UTR selection is regulated, influencing PAR-5 protein abundance. Alternative splicing underlies the selection of par-5 3' UTR isoforms. 3' UTR splicing is enhanced by the SR protein kinase SPK-1, and accordingly, SPK-1 is required for wild-type PAR-5 levels and PAR domain size. Precise regulation of par-5 isoform selection is essential for polarization when the posterior PAR network is compromised. Together, strict control of PAR-5 protein levels and feedback from polarity to par-5 3' UTR selection confer robustness to embryo polarization.
    Cell Reports 09/2014; 8(5). DOI:10.1016/j.celrep.2014.08.004 · 8.36 Impact Factor
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