MAP Kinase Signaling Antagonizes PAR-1 Function During Polarization of the Early <i>Caenorhabditis elegans</i> Embryo

Spilker, Annina C.; Rabilotta, Alexia; Zbinden, Caroline; Labbé, Jean-Claude; Gotta, Monica

doi:10.1534/genetics.109.106716

Cited by 23 publications

(26 citation statements)

References 49 publications

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“…Interestingly, MAPK signaling antagonizes PAR1 signaling during embryonic polarization in C. elegans [54]. It is possible that MAPK signaling is linked to cell polarization, because MARK2 (also known as EMK), the mouse homolog of PAR1, localizes in the basolateral domain, complementary to the apical localization of PARD6B and PRKCZ at the 8-and 16-cell stage [22].…”

Section: Discussionmentioning

confidence: 99%

Cell Polarity Regulator PARD6B Is Essential for Trophectoderm Formation in the Preimplantation Mouse Embryo1

Alarcón

2010

Biology of Reproduction

135

125

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In preimplantation mouse development, the first cell lineages to be established are the trophectoderm (TE) and inner cell mass. TE possesses epithelial features, including apical-basal cell polarity and intercellular junctions, which are crucial to generate a fluid-filled cavity in the blastocyst. Homologs of the partitioning defective (par) genes in Caenorhabditis elegans are critical regulators of cell polarity. However, their roles in regulating TE differentiation and blastocyst formation remain unclear. Here, the role of mouse Pard6b, a homolog of par-6 gene and a component of the PAR-atypical protein kinase C (aPKC) complex, was investigated. Pard6b expression was knocked down by microinjecting RNA interference construct into zygotes. Pard6b-knockdown embryos cleaved and compacted normally but failed to form the blastocyst cavity. The cavitation failure is likely the result of defective intercellular junctions, because Pard6b knockdown caused abnormal distribution of actin filaments and TJP1 (ZO-1) tight junction (TJ) protein and interfered with cavitation in chimeras containing cells from normal embryos. Defective TJ formation may be caused by abnormal cell polarization, because the apical localization of PRKCZ (aPKCzeta) was absent in Pard6b-knockdown embryos. Pard6b knockdown also diminished the expression of CDX2, a TE-lineage transcription factor, in the outer cells. TEAD4, a transcriptional activator that is required for Cdx2 expression and cavity formation, was not essential for the transcription of Pard6b. Taken together, Pard6b is necessary for blastocyst morphogenesis, particularly the development of TE-specific features-namely, the apical-basal cell polarity, formation of TJ, paracellular permeability sealing, and up-regulated expression of Cdx2.

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Section: Discussionmentioning

confidence: 99%

Cell Polarity Regulator PARD6B Is Essential for Trophectoderm Formation in the Preimplantation Mouse Embryo1

Alarcón

2010

Biology of Reproduction

135

125

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“…These par mutations each result in a single amino acid substitution in the mutant proteins (Watts et al 2000;Spilker et al 2009) and the mutant embryos show typical par phenotypes at the nonpermissive temperature of 25°. Under semipermissive conditions, 19°for par-1(zu310) and 17°f…”

Section: Identification Of Enhancers Of Conditional Par-1 or Par-4 Mumentioning

confidence: 99%

“…RNAi screens have identified suppressors of polarity mutants (Labbe et al 2006;Spilker et al 2009) and RNAi screens for synthetic lethality with conditional lethal mutants involved in morphogenesis (Sawyer et al 2011), embryo elongation (Zahreddine et al 2010), and neddylation (Dorfman et al 2009) have also proved fruitful. (For a general discussion of RNAi screens, see Boutros and Ahringer 2008.…”

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confidence: 99%

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

2012

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The par genes of Caenorhabditis elegans are essential for establishment and maintenance of early embryo polarity and their homologs in other organisms are crucial polarity regulators in diverse cell types. Forward genetic screens and simple RNAi depletion screens have identified additional conserved regulators of polarity in C. elegans; genes with redundant functions, however, will be missed by these approaches. To identify such genes, we have performed a genome-wide RNAi screen for enhancers of lethality in conditional par-1 and par-4 mutants. We have identified 18 genes for which depletion is synthetically lethal with par-1 or par-4, or both, but produces little embryo lethality in wild type. Fifteen of the 18 genes identified in our screen are not previously known to function in C. elegans embryo polarity and 11 of them also increase lethality in a par-2 mutant. Among the strongest synthetic lethal genes, polarity defects are more apparent in par-2 early embryos than in par-1 or par-4, except for strd-1(RNAi), which enhances early polarity phenotypes in all three mutants. One strong enhancer of par-1 and par-2 lethality, F25B5.2, corresponds to nop-1, a regulator of actomyosin contractility for which the molecular identity was previously unknown. Other putative polarity enhancers identified in our screen encode cytoskeletal and membrane proteins, kinases, chaperones, and sumoylation and deubiquitylation proteins. Further studies of these genes should give mechanistic insight into pathways regulating establishment and maintenance of cell polarity.T HE regulation of cell polarity is essential for development and function of diverse cell types. The six par genes, first identified for their role in regulating polarity in the one-cell Caenorhabditis elegans embryo (Kemphues et al. 1988;Watts et al. 1996;Morton et al. 2002) are central to the coordinated organization of polarity in a variety of cell types, including epithelial tissues, migrating cells, neurons, and oocytes (reviewed in St Johnston and Ahringer 2010; Nance and Zallen 2011). In the C. elegans zygote, the par genes are required for segregation of cytoplasmic components including developmental determinants and cell timing regulators. Because of the high degree of conservation of the PAR proteins and their partners, C. elegans remains an excellent system for identifying key regulators of polarity.The genes par-1 and par-4 encode conserved serinethreonine kinases. PAR-1 is related to mammalian MARK kinases; PAR-4 is the C. elegans homolog of LKB1, the upstream regulatory kinase of the AMPK kinase family, including MARKs (reviewed by Alessi et al. 2006). LKB1 is a known tumor suppressor for which mutations lead to Peutz-Jegher syndrome and predisposition to cancer in epithelial tissues such as the intestine (Hemminki et al. 1998;Jenne et al. 1998). In the C. elegans embryo, PAR-1 and PAR-4 are essential for asymmetric localization of P granules and developmental regulators such as MEX-5 and PIE-1 and for asynchronous cell divisions of the early b...

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“…Purified MBP::SPAT-1 was injected into rabbits (Charles River Laboratories). All stainings were performed as described (Spilker et al, 2009). The following primary antibodies were used: anti-tubulin (mouse DM1A, Sigma, 1:1000), anti-SPAT-1 (rabbit, 1:35), anti-PAR-2 (rabbit, 1:50), anti-HA (mouse, 1:200, Sigma) and anti-PLK-1 [rabbit, 1:1000 (Chase et al, 2000)].…”

Section: Antibody Production and Immunostainingmentioning

confidence: 99%

SPAT-1/Bora acts with Polo-like kinase 1 to regulate PAR polarity and cell cycle progression

2010

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During asymmetric cell division, cell polarity and cell cycle progression are tightly coordinated, yet mechanisms controlling both these events are poorly understood. Here we show that the Bora homologue SPAT-1 regulates both PAR polarity and cell cycle progression in C. elegans embryos. We find that, similarly to mammalian cells, SPAT-1 acts with PLK-1 and not with the mitotic kinase Aurora A (AIR-1), as shown in Drosophila. SPAT-1 binds to PLK-1, and depletion of SPAT-1 or PLK-1 leads to similar cell division defects in early embryos, which differ from the defects caused by depletion of AIR-1. Additionally, SPAT-1 and PLK-1 depletion causes impaired polarity with abnormal length of the anterior and posterior PAR domains, and partial plk-1(RNAi) or spat-1(RNAi), but not air-1(RNAi), can rescue the lethality of a par-2 mutant. SPAT-1 is enriched in posterior cells, and this enrichment depends on PAR polarity and PLK-1. Taken together, our data suggest a model in which SPAT-1 promotes the activity of PLK-1 to regulate both cell polarity and cell cycle timing during asymmetric cell division, providing a link between these two processes

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MAP Kinase Signaling Antagonizes PAR-1 Function During Polarization of the Early Caenorhabditis elegans Embryo

Cited by 23 publications

References 49 publications

Cell Polarity Regulator PARD6B Is Essential for Trophectoderm Formation in the Preimplantation Mouse Embryo1

Cell Polarity Regulator PARD6B Is Essential for Trophectoderm Formation in the Preimplantation Mouse Embryo1

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

SPAT-1/Bora acts with Polo-like kinase 1 to regulate PAR polarity and cell cycle progression

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