Translation of Polarity Cues into Asymmetric Spindle Positioning in
            <i>Caenorhabditis elegans</i>
            Embryos

Colombo, Kelly; Grill, Stephan W.; Kimple, Randall J.; Willard, Francis S.; Siderovski, David P.; Gönczy, Pierre

doi:10.1126/science.1084146

Cited by 270 publications

(364 citation statements)

References 23 publications

Supporting

Mentioning

339

Contrasting

Order By: Relevance

“…A notable exception to the multiple GoLocos present in Pins-like proteins is the C. elegans Pins homologue GPR-1/2, which contains a single GoLoco domain. The lack of multiple GoLocos in GPR-1/2 may be consistent with their more limited role in C. elegans asymmetric cell division, where they regulate spindle positioning but not cortical polarity (25)(26)(27)). …”

Section: The Pins Intramolecular Interaction As a Mechanism For Localmentioning

confidence: 77%

Gαi generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts

Nipper

Siller

Smith

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

108

View full text Add to dashboard Cite

Drosophila neuroblasts divide asymmetrically by aligning their mitotic spindle with cortical cell polarity to generate distinct sibling cell types. Neuroblasts asymmetrically localize G␣i, Pins, and Mud proteins; Pins/G␣i direct cortical polarity, whereas Mud is required for spindle orientation. It is currently unknown how G␣i-Pins-Mud binding is regulated to link cortical polarity with spindle orientation. Here, we show that Pins forms a ''closed'' state via intramolecular GoLoco-tetratricopeptide repeat (TPR) interactions, which regulate Mud binding. Biochemical, genetic, and live imaging experiments show that G␣i binds to the first of three Pins GoLoco motifs to recruit Pins to the apical cortex without ''opening'' Pins or recruiting Mud. However, G␣i and Mud bind cooperatively to the Pins GoLocos 2/3 and tetratricopeptide repeat domains, respectively, thereby restricting Pins-Mud interaction to the apical cortex and fixing spindle orientation. We conclude that Pins has multiple activity states that generate cortical polarity and link it with mitotic spindle orientation.cell polarity ͉ cell signaling ͉ differentiation ͉ protein-protein interactions I n complex, multicellular organisms, differentiated cell types are needed to perform diverse functions. One common mechanism for cellular differentiation is asymmetric cell division, in which the mitotic spindle is aligned with the cell polarity axis to generate molecularly distinct sibling cells (1-4). Asymmetric divisions have been proposed to regulate stem cell pool size during development, adult tissue homeostasis, and the uncontrolled proliferation observed in cancer (5). Thus, understanding how the mitotic spindle is coupled to the cell polarity axis is relevant to stem cell and cancer biology. Here, we investigate this question in Drosophila neuroblasts, a model system for studying asymmetric cell division.Drosophila neuroblasts are stem cell-like progenitors that divide asymmetrically to produce a larger self-renewing neuroblast and a smaller ganglion mother cell (GMC) that differentiates into neurons or glia (3). Mitotic neuroblasts segregate factors that promote neuroblast self-renewal to their apical cortex and differentiation factors to their basal cortex. Precise alignment of the mitotic spindle with the neuroblast apical/basal polarity is required for asymmetric cell division and proper brain development: spindle misalignment leads to symmetric cell divisions that expand the neuroblast population and brain size (6-8).

show abstract

Section: The Pins Intramolecular Interaction As a Mechanism For Localmentioning

confidence: 77%

Gαi generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts

Nipper

Siller

Smith

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

108

View full text Add to dashboard Cite

show abstract

“…In addition, G-protein subunits and such accessory proteins may be located in intracellular domains as well as at the plasma membrane (2)(3)(4)(5). Such observations have broad conceptual and functional implications as they also suggest that G-proteins are processing intracellular signals that do not involve a GPCR at the cell surface (1,6,7), as recently demonstrated for the role of G-proteins and such accessory proteins in asymmetric positioning of the mitotic spindle in the one-cell Caenorhabditis elegans embryo (8,9).…”

mentioning

confidence: 81%

Identification and Characterization of AGS4

Cao

Cismowski

Sato

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Activators of G-protein signaling 1-3 (AGS1-3) were identified in a functional screen of mammalian cDNAs that activated G-protein signaling in the absence of a receptor. We report the isolation and characterization of an additional AGS protein (AGS4) from a human prostate leiomyosarcoma cDNA library. AGS4 is identical to G18.1b, which is encoded by a gene within the major histocompatibility class III region of chromosome 6. The activity of AGS4 in the yeast-based functional screen was selective for G i2 /G i3 and independent of guaninenucleotide exchange by G i ␣. RNA blots indicated enrichment of AGS4/G18.1b mRNA in heart, placenta, lung, and liver. Immunocytochemistry with AGS4/G18.1b-specific antisera indicated a predominant nonhomogeneous, extranuclear distribution within the cell following expression in COS7 or Chinese hamster ovary cells. AGS4/ G18.1b contains three G-protein regulatory motifs downstream of an amino terminus domain with multiple prolines. Glutathione S-transferase (GST)-AGS4/G18.1b fusion proteins interacted with purified G i ␣, and peptides derived from each of the G-protein regulatory motifs inhibited guanosine 5 -3-O-(thio)triphosphate (GTP␥S) binding to purified G i ␣ 1 . AGS4/G18.1b was also complexed with G i ␣ 3 in COS7 cell lysates following cell transfection. However, AGS4/G18.1b did not alter the generation of inositol phosphates in COS7 cells cotransfected with the G␤␥-regulated effector phospholipase C-␤2. These data suggest either that an additional signal is required to position AGS4/G18.1b in the proper cellular location where it can access heterotrimer and promote subunit dissociation or that AGS4 serves as an alternative binding partner for G i ␣ independent of G␤␥ participating in G-protein signaling events that are independent of classical G-protein-coupled receptors at the cell surface.

show abstract

“…In C. elegans one-cell embryos, polarity cues result in an unequally increased pulling force on the posterior spindle, accompanied by vigorous rocking and elongation of the spindle. The GoLoco-containing proteins GPR-1 and GPR-2, as well as the cortical Gα subunits GOA-1 and GPA-16 are essential for generation of proper pulling forces and thus asymmetric spindle positioning [12]. In MDCK cells, LGN and Gαi expression induced pronounced chromosome oscillation during mitosis, which is likely a result of unbalanced pulling forces acting on the mitotic apparatus through the aster microtubules [16].…”

Section: Discussionmentioning

confidence: 99%

“…In Drosophila neuroblasts, Pins regulates apical-basal spindle orientation and asymmetric cell division [11]. In Caenorhabditis elegans one-cell embryos, the Pins functional counterparts GPR-1/2 are essential for translating polarity cues into asymmetric spindle positioning [11,12]. Mammals have two Pins homologs, AGS3 (Activator of G-protein Signaling 3) and LGN (named after ten Leucine-Glycine-Asparagine tripeptides in its N-terminal region).…”

Section: Introductionmentioning

confidence: 99%

Pins homolog LGN regulates meiotic spindle organization in mouse oocytes

Guo

Gao

2009

Cell Res

View full text Add to dashboard Cite

Mouse oocytes undergo polarization during meiotic maturation, and this polarization is essential for asymmetric cell divisions that maximize retention of maternal components required for early development. Without conventional centrosomes, the meiotic spindle has less focused poles and is barrel-shaped. The migration of meiotic spindles to the cortex is accompanied by a local reorganization and polarization of the cortex. LGN is a conserved protein involved in cell polarity and regulation of spindle organization. In the present study, we characterized the localization dynamics of LGN during mouse oocyte maturation and analyzed the effects of LGN upregulation and downregulation on meiotic spindle organization. At the germinal vesicle stage, LGN is distributed both cytoplasmically and at the cortex. During maturation, LGN localizes to the meiotic spindle apparatus and cortical LGN becomes less concentrated at the actin cap region. Excessive LGN induces meiotic spindle organization defects by elongating the spindle and enhancing pole focusing, whereas depletion of LGN by RNA interference results in meiotic spindle deformation and chromosome misalignment. Furthermore, the N-terminus of LGN has the ability of full-length LGN to regulate spindle organization, whereas the C-terminus of LGN controls cortical localization and polarization. Our results reveal that LGN is cortically polarized in mouse oocytes and is critical for meiotic spindle organization.

show abstract

Translation of Polarity Cues into Asymmetric Spindle Positioning in Caenorhabditis elegans Embryos

Cited by 270 publications

References 23 publications

Gαi generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts

Gαi generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts

Identification and Characterization of AGS4

Pins homolog LGN regulates meiotic spindle organization in mouse oocytes

Contact Info

Product

Resources

About