Article

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

ABSTRACT

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.
    Full-text · Article · Oct 2015 · Developmental Cell
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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: eLife digest Individuals of the same species have similar, but generally not identical, DNA sequences. This ‘genetic variation’ is due to random changes in the DNA—known as mutations—that occur among individuals. These mutations may be passed on to these individuals' offspring, who in turn pass them on to their descendants. Some of these mutations may have a positive or negative effect on the ability of the organisms to survive and reproduce, but others may have no effect at all. The process by which an embryo forms (which is called embryogenesis) follows a precisely controlled series of events. Within the same species, there is genetic variation in the DNA that programs embryogenesis, but it is not clear what effect this variation has on how the embryo develops. Here, Paaby et al. adapted a genetics technique called a ‘modifier screen’ to study how genetic variation affects the development of a roundworm known as Caenorhabditis elegans. The experiments show that populations of worms harbor a lot of genetic variation that affects how they tolerate the loss of an important gene. One by one, Paaby et al. interrupted the activity of specific genes that embryos need in order to develop. How this affected the embryo, and whether or not it was able to survive, was due in large part to the naturally-occurring genetic variation in other genes in these worms. Paaby et al.'s findings serve as a reminder that the effect of a mutation depends on other DNA sequences in the organism. In humans, for example, a gene that causes a genetic disease may produce severe symptoms in one patient but mild symptoms in another. Future experiments will reveal the details of how genetic variation affects embryogenesis, which may also provide new insights into how complex processes in animals evolve over time. DOI: http://dx.doi.org/10.7554/eLife.09178.002
    Full-text · Article · Aug 2015 · eLife Sciences
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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.
    Full-text · Article · Sep 2014 · Cell Reports
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