scholarly journals Junctional tumor suppressors interact with 14-3-3 proteins to control planar spindle alignment

2019 ◽  
Vol 218 (6) ◽  
pp. 1824-1838 ◽  
Author(s):  
Yu-ichiro Nakajima ◽  
Zachary T. Lee ◽  
Sean A. McKinney ◽  
Selene K. Swanson ◽  
Laurence Florens ◽  
...  
Keyword(s):  
Cell Fate ◽  
Tumor Suppressors ◽  
Mitotic Spindle ◽  
Wing Disc ◽  
Spindle Orientation ◽  
Epithelial Proliferation ◽  
Tissue Architecture ◽  
Drosophila Wing ◽  
Discs Large

Proper orientation of the mitotic spindle is essential for cell fate determination, tissue morphogenesis, and homeostasis. During epithelial proliferation, planar spindle alignment ensures the maintenance of polarized tissue architecture, and aberrant spindle orientation can disrupt epithelial integrity. Nevertheless, in vivo mechanisms that restrict the mitotic spindle to the plane of the epithelium remain poorly understood. Here we show that the junction-localized tumor suppressors Scribbled (Scrib) and Discs large (Dlg) control planar spindle orientation via Mud and 14-3-3 proteins in the Drosophila wing disc epithelium. During mitosis, Scrib is required for the junctional localization of Dlg, and both affect mitotic spindle movements. Using coimmunoprecipitation and mass spectrometry, we identify 14-3-3 proteins as Dlg-interacting partners and further report that loss of 14-3-3s causes both abnormal spindle orientation and disruption of epithelial architecture as a consequence of basal cell delamination and apoptosis. Combined, these biochemical and genetic analyses indicate that 14-3-3s function together with Scrib, Dlg, and Mud during planar cell division.

scholarly journals Interaction between Discs large and Pins/LGN/GPSM2: A comparison across species

Biology Open ◽  
2021 ◽  
Author(s):  
Emily A. Schiller ◽  
Dan T. Bergstralh
Keyword(s):  
Cell Fate ◽  
Mitotic Spindle ◽  
Evolutionary History ◽  
Scaffolding Protein ◽  
Spindle Orientation ◽  
C Elegans ◽  
Discs Large ◽  
Canonical Pathways ◽  
History Of ◽  
Multicellular Organisms

The orientation of the mitotic spindle determines the direction of cell division, and therefore contributes to tissue shape and cell fate. Interaction between the multifunctional scaffolding protein Discs large (Dlg) and the canonical spindle orienting factor GPSM2 (called Pins in Drosophila and LGN in vertebrates) has been established in bilaterian models, but its function remains unclear. We used a phylogenetic approach to test whether the interaction is obligate in animals, and in particular whether Pins/LGN/GPSM2 evolved in multicellular organisms as a Dlg-binding protein. We show that Dlg diverged in C. elegans and the syncytial sponge O. minuta and propose that this divergence may correspond to differences in spindle orientation requirements between these organisms and the canonical pathways described in bilaterians. We also demonstrate that Pins/LGN/GPSM2 is present in basal animals, but the established Dlg-interaction site cannot be found in either Placozoa or Porifera. Our results suggest that the interaction between Pins/LGN/GPSM2 and Dlg appeared in Cnidaria, and we therefore speculate that it may have evolved to promote accurate division orientation in the nervous system. This work reveals the evolutionary history of the Pins/LGN/GPSM2-Dlg interaction and suggests new possibilities for its importance in spindle orientation during epithelial and neural tissue development.

scholarly journals Strabismus regulates asymmetric cell divisions and cell fate determination in the mouse brain

2009 ◽  
Vol 185 (1) ◽  
pp. 59-66 ◽  
Author(s):  
Blue B. Lake ◽  
Sergei Y. Sokol
Keyword(s):  
Cell Fate ◽  
Mitotic Spindle ◽  
Neural Progenitors ◽  
Spindle Orientation ◽  
Asymmetric Distribution ◽  
Cell Fate Determination ◽  
Mitotic Apparatus ◽  
Fate Determination

The planar cell polarity (PCP) pathway organizes the cytoskeleton and polarizes cells within embryonic tissue. We investigate the relationship between PCP signaling and cell fate determination during asymmetric division of neural progenitors (NPs) in mouse embryos. The cortex of Lp/Lp (Loop-tail) mice deficient in the essential PCP mediator Vangl2, homologue of Drosophila melanogaster Strabismus (Stbm), revealed precocious differentiation of neural progenitors into early-born neurons at the expense of late-born neurons and glia. Although Lp/Lp NPs were easily maintained in vitro, they showed premature differentiation and loss of asymmetric distribution of Leu-Gly-Asn–enriched protein (LGN)/partner of inscuteable (Pins), a regulator of mitotic spindle orientation. Furthermore, we observed a decreased frequency in asymmetric distribution of the LGN target nuclear mitotic apparatus protein (NuMa) in Lp/Lp cortical progenitors in vivo. This was accompanied by an increase in the number of vertical cleavage planes typically associated with equal daughter cell identities. These findings suggest that Stbm/Vangl2 functions to maintain cortical progenitors and regulates mitotic spindle orientation during asymmetric divisions in the vertebrate brain.

scholarly journals Interaction between Discs large and GPSM2: A Comparison Across Species

2021 ◽  
Author(s):  
Emily Schiller ◽  
Dan T Bergstralh
Keyword(s):  
Cell Fate ◽  
Mitotic Spindle ◽  
Evolutionary History ◽  
Scaffolding Protein ◽  
Spindle Orientation ◽  
C Elegans ◽  
Discs Large ◽  
Canonical Pathways ◽  
History Of ◽  
Multicellular Organisms

The orientation of the mitotic spindle determines the direction of cell division, and therefore contributes to tissue shape and cell fate. Interaction between the multifunctional scaffolding protein Discs large (Dlg) and the canonical spindle orienting factor GPSM2 (also called Pins in Drosophila and LGN in vertebrates) has been established in bilaterian models, but its function remains unclear. We used a phylogenetic approach to test whether the interaction is obligate in animals, and in particular whether GPSM2 evolved in multicellular organisms as a Dlg-binding protein. We show that Dlg diverged in C. elegans and the syncytial sponge O. minuta and propose that this divergence may correspond to differences in spindle orientation requirements between these organisms and the canonical pathways described in bilaterians. We also demonstrate that GPSM2 is present in basal animals, but the established Dlg-interaction site cannot be found in either Placozoa or Porifera. Our results suggest that the interaction between GPSM2 and Dlg appeared in Cnidaria, and we therefore speculate that it may have evolved to promote accurate division orientation in the nervous system. This work reveals the evolutionary history of the GPSM2/Dlg interaction and suggests new possibilities for its importance in spindle orientation during epithelial and neural tissue development.

scholarly journals NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lindsey Seldin ◽  
Andrew Muroyama ◽  
Terry Lechler
Keyword(s):  
Cell Fate ◽  
Mitotic Spindle ◽  
Cell Types ◽  
Epidermal Differentiation ◽  
Spindle Orientation ◽  
Direct Function ◽  
Spindle Positioning ◽  
Adult Mice ◽  
Neonatal Lethality ◽  
The Matrix

Mitotic spindle orientation is used to generate cell fate diversity and drive proper tissue morphogenesis. A complex of NuMA and dynein/dynactin is required for robust spindle orientation in a number of cell types. Previous research proposed that cortical dynein/dynactin was sufficient to generate forces on astral microtubules (MTs) to orient the spindle, with NuMA acting as a passive tether. In this study, we demonstrate that dynein/dynactin is insufficient for spindle orientation establishment in keratinocytes and that NuMA’s MT-binding domain, which targets MT tips, is also required. Loss of NuMA-MT interactions in skin caused defects in spindle orientation and epidermal differentiation, leading to neonatal lethality. In addition, we show that NuMA-MT interactions are also required in adult mice for hair follicle morphogenesis and spindle orientation within the transit-amplifying cells of the matrix. Loss of spindle orientation in matrix cells results in defective differentiation of matrix-derived lineages. Our results reveal an additional and direct function of NuMA during mitotic spindle positioning, as well as a reiterative use of spindle orientation in the skin to build diverse structures.

scholarly journals The Rap1–Rgl–Ral signaling network regulates neuroblast cortical polarity and spindle orientation

2011 ◽  
Vol 195 (4) ◽  
pp. 553-562 ◽  
Author(s):  
Ana Carmena ◽  
Aljona Makarova ◽  
Stephan Speicher
Keyword(s):  
Cell Fate ◽  
Asymmetric Cell Division ◽  
Signaling Network ◽  
Spindle Orientation ◽  
Nucleotide Exchange ◽  
Loss Of Function ◽  
Axis Orientation ◽  
Division Axis ◽  
Guanosine Triphosphatase

A crucial first step in asymmetric cell division is to establish an axis of cell polarity along which the mitotic spindle aligns. Drosophila melanogaster neural stem cells, called neuroblasts (NBs), divide asymmetrically through intrinsic polarity cues, which regulate spindle orientation and cortical polarity. In this paper, we show that the Ras-like small guanosine triphosphatase Rap1 signals through the Ral guanine nucleotide exchange factor Rgl and the PDZ protein Canoe (Cno; AF-6/Afadin in vertebrates) to modulate the NB division axis and its apicobasal cortical polarity. Rap1 is slightly enriched at the apical pole of metaphase/anaphase NBs and was found in a complex with atypical protein kinase C and Par6 in vivo. Loss of function and gain of function of Rap1, Rgl, and Ral proteins disrupt the mitotic axis orientation, the localization of Cno and Mushroom body defect, and the localization of cell fate determinants. We propose that the Rap1–Rgl–Ral signaling network is a novel mechanism that cooperates with other intrinsic polarity cues to modulate asymmetric NB division.

scholarly journals Eph signaling controls mitotic spindle orientation and cell proliferation in neuroepithelial cells

2019 ◽  
Vol 218 (4) ◽  
pp. 1200-1217 ◽  
Author(s):  
Maribel Franco ◽  
Ana Carmena
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
Mitotic Spindle ◽  
Optic Lobe ◽  
Spindle Orientation ◽  
Intercellular Signaling ◽  
Neuroepithelial Cells ◽  
Core Components ◽  
Conserved Core ◽  
Activity Dependent

Mitotic spindle orientation must be tightly regulated during development and adult tissue homeostasis. It determines cell-fate specification and tissue architecture during asymmetric and symmetric cell division, respectively. Here, we uncover a novel role for Ephrin–Eph intercellular signaling in controlling mitotic spindle alignment in Drosophila optic lobe neuroepithelial cells through aPKC activity–dependent myosin II regulation. We show that conserved core components of the mitotic spindle orientation machinery, including Discs Large1, Mud/NuMA, and Canoe/Afadin, mislocalize in dividing Eph mutant neuroepithelial cells and produce spindle alignment defects in these cells when they are down-regulated. In addition, the loss of Eph leads to a Rho signaling–dependent activation of the PI3K–Akt1 pathway, enhancing cell proliferation within this neuroepithelium. Hence, Eph signaling is a novel extrinsic mechanism that regulates both spindle orientation and cell proliferation in the Drosophila optic lobe neuroepithelium. Similar mechanisms could operate in other Drosophila and vertebrate epithelia.

scholarly journals An Assay to Detect In Vivo Y Chromosome Loss in Drosophila Wing Disc Cells

2012 ◽  
Vol 2 (9) ◽  
pp. 1095-1102 ◽  
Author(s):  
Janos Szabad ◽  
Hugo J. Bellen ◽  
Koen J. T. Venken
Keyword(s):  
Y Chromosome ◽  
Wing Disc ◽  
Chromosome Loss ◽  
Drosophila Wing ◽  
Disc Cells

scholarly journals Microvilli-derived Extracellular Vesicles Govern Morphogenesis in Drosophila wing epithelium

2020 ◽  
Author(s):  
Ilse Hurbain ◽  
Anne-Sophie Macé ◽  
Maryse Romao ◽  
Lucie Sengmanivong ◽  
Laurent Ruel ◽  
...  
Keyword(s):  
Long Range ◽  
Extracellular Vesicles ◽  
Cell Biology ◽  
Extracellular Vesicle ◽  
Wing Disc ◽  
Cellular Mechanisms ◽  
Long Distance ◽  
Drosophila Wing ◽  
And Function

ABSTRACTThe regulation and coordination of developmental processes involves the secretion of morphogens and membrane carriers, including extracellular vesicles, which facilitate their transport over long distance. The long-range activity of the Hedgehog morphogen is conveyed by extracellular vesicles. However, the site and the molecular basis of their biogenesis remains unknown. By combining fluorescence and electron microscopy combined with genetics and cell biology approaches, we investigated the origin and the cellular mechanisms underlying extracellular vesicle biogenesis, and their contribution to Drosophila wing disc development, exploiting Hedgehog as a long-range morphogen. We show that microvilli of Drosophila wing disc epithelium are the site of generation of small extracellular vesicles that transport Hedgehog across the tissue. This process requires the Prominin-like protein, whose activity, together with interacting cytoskeleton components and lipids, is critical for maintaining microvilli integrity and function in secretion. Our results provide the first evidence that microvilli-derived extracellular vesicles contribute to Hedgehog long-range signaling activity highlighting their physiological significance in tissue development in vivo.

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