A Genome-Wide RNAi Screen for Enhancers of <i>par</i> Mutants Reveals New Contributors to Early Embryonic Polarity in <i>Caenorhabditis elegans</i>

Morton, Diane G.; Hoose, Wendy A.; Kemphues, Kenneth J.

doi:10.1534/genetics.112.143727

Cited by 24 publications

(31 citation statements)

References 98 publications

(125 reference statements)

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“…PIG-1 and PAR-1 may function together with PAR-4 in this asymmetric division. It is noteworthy that pig-1 has recently been shown to significantly enhance the embryonic lethal phenotype of par-1 mutants (Morton et al 2012). Our results and those of Morton et al suggest that PIG-1 and PAR-1 could act together in multiple asymmetric divisions.…”

Section: Discussionsupporting

confidence: 73%

Caenorhabditis elegans PIG-1/MELK Acts in a Conserved PAR-4/LKB1 Polarity Pathway to Promote Asymmetric Neuroblast Divisions

et al. 2013

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Asymmetric cell divisions produce daughter cells with distinct sizes and fates, a process important for generating cell diversity during development. Many Caenorhabditis elegans neuroblasts, including the posterior daughter of the Q cell (Q.p), divide to produce a larger neuron or neuronal precursor and a smaller cell that dies. These size and fate asymmetries require the gene pig-1, which encodes a protein orthologous to vertebrate MELK and belongs to the AMPK-related family of kinases. Members of this family can be phosphorylated and activated by the tumor suppressor kinase LKB1, a conserved polarity regulator of epithelial cells and neurons. In this study, we present evidence that the C. elegans orthologs of LKB1 (PAR-4) and its partners STRAD (STRD-1) and MO25 (MOP-25.2) regulate the asymmetry of the Q.p neuroblast division. We show that PAR-4 and STRD-1 act in the Q lineage and function genetically in the same pathway as PIG-1. A conserved threonine residue (T169) in the PIG-1 activation loop is essential for PIG-1 activity, consistent with the model that PAR-4 (or another PAR-4-regulated kinase) phosphorylates and activates PIG-1. We also demonstrate that PIG-1 localizes to centrosomes during cell divisions of the Q lineage, but this localization does not depend on T169 or PAR-4. We propose that a PAR-4-STRD-1 complex stimulates PIG-1 kinase activity to promote asymmetric neuroblast divisions and the generation of daughter cells with distinct fates. Changes in cell fate may underlie many of the abnormal behaviors exhibited by cells after loss of PAR-4 or LKB1.A SYMMETRIC cell divisions produce daughter cells with distinct fates, a process important for generating cell diversity in organisms as different as bacteria, plants, and animals. In Caenorhabditis elegans, asymmetric divisions of neuroblasts often produce cells fated to die. The posterior daughter of the Q cell (Q.p) neuroblasts, for example, divide to produce a neuronal precursor and a cell that dies, but how this fate asymmetry is generated in these divisions is poorly understood. PIG-1 regulates asymmetric neuroblast divisions that generate apoptotic cells by controlling spindle positioning, myosin distribution, and daughter cell fate (Cordes et al. 2006;Ou et al. 2010). PIG-1 is the sole C. elegans ortholog of MELK (maternal embryonic leucine zipper kinase), a serine/ threonine kinase that has been implicated in many developmental processes including stem cell renewal, apoptosis, cell cycle progression, and spliceosome assembly (Davezac et al. 2002;Vulsteke et al. 2004;Nakano et al. 2005;Lin et al. 2007;Jung et al. 2008). MELK and PIG-1 represent a subgroup of a large family of serine/threonine kinases that include molecules like PAR-1 and SAD-1, which regulate cell polarity, and AMPKs, which regulate metabolic processes (Bright et al. 2009). These family members are often regulated directly by the LKB1 kinase (Lizcano et al. 2004).Loss of the tumor suppressor LKB1 causes Peutz-Jeghers syndrome, a disease in humans that is characterized...

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Section: Discussionsupporting

confidence: 73%

Caenorhabditis elegans PIG-1/MELK Acts in a Conserved PAR-4/LKB1 Polarity Pathway to Promote Asymmetric Neuroblast Divisions

et al. 2013

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“…math-33 was identified in an RNA interference (RNAi)-based screen for enhancers of embryonic lethality of weak par-1 and par-4 mutants [31]. math-33 encodes a protein with a meprin and TRAF homology (MATH) domain, and a ubiquitin carboxy-terminal hydrolase (UCH) domain.…”

Section: Resultsmentioning

confidence: 99%

Deubiquitylation Machinery Is Required for Embryonic Polarity in Caenorhabditis elegans

McCloskey¹,

Kemphues

2012

PLoS Genet

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The Caenorhabditis elegans one-cell embryo polarizes in response to a cue from the paternally donated centrosome and asymmetrically segregates cell fate determinants that direct the developmental program of the worm. We have found that genes encoding putative deubiquitylating enzymes (DUBs) are required for polarization of one-cell embryos. Maternal loss of the proteins MATH-33 and USP-47 leads to variable inability to correctly establish and maintain asymmetry as defined by posterior and anterior polarity proteins PAR-2 and PAR-3. The first observable defect is variable positioning of the centrosome with respect to the cell cortex and the male pronucleus. The severity of the polarity defects correlates with distance of the centrosome from the cortex. Furthermore, polarity defects can be bypassed by mutations that bring the centrosome in close proximity to the cortex. In addition we find that polarity and centrosome positioning defects can be suppressed by compromising protein turnover. We propose that the DUB activity of MATH-33 and USP-47 stabilizes one or more proteins required for association of the centrosome with the cortex. Because these DUBs are homologous to two members of a group of DUBs that act in fission yeast polarity, we tested additional members of that family and found that another C. elegans DUB gene, usp-46, also contributes to polarity. Our finding that deubiquitylating enzymes required for polarity in Schizosaccharomyces pombe are also required in C. elegans raises the possibility that these DUBs act through an evolutionarily conserved mechanism to control cell polarity.

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“…pig-1 mutations could, in this model, enhance the differentiation of the “undead” cells towards their adhesive sister cell fate, thereby preventing shedding. PIG-1 has been implicated in the control of asymmetric cell division[59,60] and plays important roles in cell fate specification throughout the embryo[61]. In the context of cell shedding, pig-1 mutants inappropriately express the α-catenin HMP-1 on the surface of would-be shed cells, and one of these cells expresses reporters specific for its sister cell progeny, the excretory cell[56].…”

Section: Pathological Cell Death Induced By Genome Lesions and Envmentioning

confidence: 99%

Noncanonical Cell Death in the Nematode Caenorhabditis elegans

Kinet

Shaham

2014

Methods in Enzymology

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The nematode Caenorhabditis. elegans has served as a fruitful setting for cell death research for over three decades. A conserved pathway of four genes, egl-1/BH3-only, ced-9/Bcl-2, ced-4/Apaf-1, and ced-3/caspase, coordinates most developmental cell deaths in C. elegans. However, other cell death forms, programmed and pathological, have also been described in this animal. Some of these share morphological and/or molecular similarities with the canonical apoptotic pathway, while others do not. Indeed, recent studies suggest the existence of an entirely novel mode of programmed developmental cell destruction that may also be conserved beyond nematodes. Here we review evidence for these noncanonical pathways. We propose that different cell death modalities can function as backup mechanisms for apoptosis, or as tailor-made programs that allow specific dying cells to be efficiently cleared from the animal.

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A Genome-Wide RNAi Screen for Enhancers of par Mutants Reveals New Contributors to Early Embryonic Polarity in Caenorhabditis elegans

Cited by 24 publications

References 98 publications

Caenorhabditis elegans PIG-1/MELK Acts in a Conserved PAR-4/LKB1 Polarity Pathway to Promote Asymmetric Neuroblast Divisions

Caenorhabditis elegans PIG-1/MELK Acts in a Conserved PAR-4/LKB1 Polarity Pathway to Promote Asymmetric Neuroblast Divisions

Deubiquitylation Machinery Is Required for Embryonic Polarity in Caenorhabditis elegans

Noncanonical Cell Death in the Nematode Caenorhabditis elegans

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