Wnt Regulates Spindle Asymmetry to Generate Asymmetric Nuclear β-Catenin in C. elegans

Sugioka, Kenji; Mizumoto, Kota; Sawa, Hitoshi

doi:10.1016/j.cell.2011.07.043

Cited by 84 publications

(120 citation statements)

References 59 publications

(77 reference statements)

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“…These functions seem to be conserved in mammals [301]. Work from the Sawa lab could now uncover that asymmetric cortical localization of the Wnt pathway component Adenomatous polyposis coli (APC) can directly regulate spindle asymmetry [302]. Strikingly, Sawa and coworkers could also reverse mutant phenotypes by manipulating spindle asymmetry with laser ablations of centrosomes, confirming that asymmetric microtubule distribution is crucial for asymmetric cell division [302].…”

Section: Microtubules: Spindles and Centrosomesmentioning

confidence: 76%

Cytoskeletal Symmetry Breaking and Chirality: From Reconstituted Systems to Animal Development

Pohl

2015

Symmetry

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Animal development relies on repeated symmetry breaking, e.g., during axial specification, gastrulation, nervous system lateralization, lumen formation, or organ coiling. It is crucial that asymmetry increases during these processes, since this will generate higher morphological and functional specialization. On one hand, cue-dependent symmetry breaking is used during these processes which is the consequence of developmental signaling. On the other hand, cells isolated from developing animals also undergo symmetry breaking in the absence of signaling cues. These spontaneously arising asymmetries are not well understood. However, an ever growing body of evidence suggests that these asymmetries can originate from spontaneous symmetry breaking and self-organization of molecular assemblies into polarized entities on mesoscopic scales. Recent discoveries will be highlighted and it will be discussed how actomyosin and microtubule networks serve as common biomechanical systems with inherent abilities to drive spontaneous symmetry breaking.

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Section: Microtubules: Spindles and Centrosomesmentioning

confidence: 76%

Cytoskeletal Symmetry Breaking and Chirality: From Reconstituted Systems to Animal Development

Pohl

2015

Symmetry

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“…The C. elegans APC homolog APR-1 regulates mitotic 591 spindle asymmetry and microtubule stability in EMS during telophase, and a 592 GFP:: APR-1 transgene, whose function after tagging was not tested, was 593 previously shown to become enriched in the anterior cortex of EMS gradually 594 during mitosis (Sugioka et al, 2011). APR-1 was also shown to affect the 595 distribution of fate determinants in the EMS daughter cells (Sugioka et al, 2011). 596…”

Section: Dhc-1/dynein Is Not Enriched Asymmetrically In Ems 514mentioning

confidence: 99%

A CRISPR Tagging-Based Screen Reveals Localized Players in Wnt-Directed Asymmetric Cell Division

et al. 2018

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Oriented cell divisions are critical to establish and maintain cell fates and tissue organization. Diverse extracellular and intracellular cues have been shown to provide spatial information for mitotic spindle positioning; however, the molecular mechanisms by which extracellular signals communicate with cells to direct mitotic spindle positioning are largely unknown. In animal cells, oriented cell divisions are often achieved by the localization of force-generating motor protein complexes to discrete cortical domains. Disrupting either these force-generating complexes or proteins that globally affect microtubule stability results in defects in mitotic positioning, irrespective of whether these proteins function as spatial cues for spindle orientation. This poses a challenge to traditional genetic dissection of this process. Therefore, as an alternative strategy to identify key proteins that act downstream of intercellular signaling, we screened the localization of many candidate proteins by inserting fluorescent tags directly into endogenous gene loci, without overexpressing the proteins. We tagged 23 candidate proteins in Caenorhabditis elegans and examined each protein’s localization in a well-characterized, oriented cell division in the four-cell-stage embryo. We used cell manipulations and genetic experiments to determine which cells harbor key localized proteins and which signals direct these localizations in vivo. We found that Dishevelled and adenomatous polyposis coli homologs are polarized during this oriented cell division in response to a Wnt signal, but two proteins typically associated with mitotic spindle positioning, homologs of NuMA and Dynein, were not detectably polarized. These results suggest an unexpected mechanism for mitotic spindle positioning in this system, they pinpoint key proteins of interest, and they highlight the utility of a screening approach based on analyzing the localization of endogenously tagged proteins.

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“…Previous models consist of variations on cytoplasmic localization of the b-catenin homologs along with the APC homolog, APR-1 (Mizumoto and Sawa 2007b;Baldwin and Phillips 2014;Gorrepati et al 2015), and that it is the shuttling of these proteins, in the presence of a polarizing Wnt signal, that facilitates POP-1 (TCF) export from the nucleus in the posterior daughter cell (Sugioka et al 2011). However, a continuing question in this area remained: Is there a nuclear mechanism that sensitizes WRM-1 to export from the nucleus in the anterior daughter?…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, both WRM-1 and SYS-1 are kept low in the nucleus of the unsignaled daughter by APR-1/APC. APR-1 negatively regulates total cellular levels of SYS-1 in a manner consistent with its degradation (Baldwin and Phillips 2014), while also lowering nuclear WRM-1 by stabilizing its cortical localization (Mizumoto and Sawa 2007a;Sugioka et al 2011). Although much has been reported on the importance of the Wnt signaling influence on seam cell asymmetric division, certain aspects remain unclear, such as the mechanism by which POP-1 asymmetry is established in the two daughter cells.…”

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confidence: 99%

Asymmetric Wnt Pathway Signaling Facilitates Stem Cell-Like Divisions via the Nonreceptor Tyrosine Kinase FRK-1 inCaenorhabditis elegans

et al. 2015

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Asymmetric cell division is critical during development, as it influences processes such as cell fate specification and cell migration. We have characterized FRK-1, a homolog of the mammalian Fer nonreceptor tyrosine kinase, and found it to be required for differentiation and maintenance of epithelial cell types, including the stem cell-like seam cells of the hypodermis. A genomic knockout of frk-1, allele ok760, results in severely uncoordinated larvae that arrest at the L1 stage and have an excess number of lateral hypodermal cells that appear to have lost asymmetry in the stem cell-like divisions of the seam cell lineage. frk-1(ok760) mutants show that there are excess lateral hypodermal cells that are abnormally shaped and smaller in size compared to wild type, a defect that could be rescued only in a manner dependent on the kinase activity of FRK-1. Additionally, we observed a significant change in the expression of heterochronic regulators in frk-1(ok760) mutants. However, frk-1(ok760) mutants do not express late, nonseam hypodermal GFP markers, suggesting the seam cells do not precociously differentiate as adult-hyp7 cells. Finally, our data also demonstrate a clear role for FRK-1 in seam cell proliferation, as eliminating FRK-1 during the L3-L4 transition results in supernumerary seam cell nuclei that are dependent on asymmetric Wnt signaling. Specifically, we observe aberrant POP-1 and WRM-1 localization that is dependent on the presence of FRK-1 and APR-1. Overall, our data suggest a requirement for FRK-1 in maintaining the identity and proliferation of seam cells primarily through an interaction with the asymmetric Wnt pathway. KEYWORDS Wnt; fer; kinase; asymmetry; development A SYMMETRIC division is a critical component of stem cell populations, ranging from organismal development to tissue maintenance during adulthood. Without asymmetric divisions early embryos would not progress toward cellular specification and adult cell types, such as blood, would lose the ability to maintain numbers through self-renewal. Particularly important to stem cell division is the capability to maintain the stem cell population via asymmetric division where one daughter cell is specified to become a certain cell type, while the other daughter cell becomes another stem cell.In the nematode Caenorhabditis elegans a stem cell-like population, called seam cells, exists in the hypodermis and undergoes a series of asymmetric divisions after each larval molt, thus facilitating postembryonic development (Sulston and Horvitz 1977). Seam cells are critical for proper formation of the hypodermis, the secreted cuticle, and other cell types derived from seam cells such as neuroblasts and glial cells. The seam cells consist of three anterior sets, H0, H1, and H2, followed by six V cells and one T cell in the posterior (Figure 1). The V cells undergo unique stem cell-like divisions during postembryonic development that lead to one anterior daughter that fuses with the hypodermal syncytial cell, hyp7, and one posterior daughte...

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Wnt Regulates Spindle Asymmetry to Generate Asymmetric Nuclear β-Catenin in C. elegans

Cited by 84 publications

References 59 publications

Cytoskeletal Symmetry Breaking and Chirality: From Reconstituted Systems to Animal Development

Cytoskeletal Symmetry Breaking and Chirality: From Reconstituted Systems to Animal Development

A CRISPR Tagging-Based Screen Reveals Localized Players in Wnt-Directed Asymmetric Cell Division

Asymmetric Wnt Pathway Signaling Facilitates Stem Cell-Like Divisions via the Nonreceptor Tyrosine Kinase FRK-1 inCaenorhabditis elegans

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