scholarly journals The interaction between the tumour suppressor Dlg1 and the MAGUK protein CASK is required for oriented cell division in mammalian epithelia

2018 ◽  
Author(s):  
Andrew P. Porter ◽  
Gavin White ◽  
Natalie A. Mack ◽  
Angeliki Malliri
Keyword(s):  
Cell Division ◽  
Epithelial Cells ◽  
3D Culture ◽  
Direct Interaction ◽  
Tumour Suppressor ◽  
Spindle Orientation ◽  
Oriented Cell Division ◽  
Cell Divisions ◽  
Microtubule Stability ◽  
Maguk Protein

AbstractOriented cell divisions are important for the formation of normal epithelial structures. Dlg1, a tumour suppressor, is required for oriented cell division in Drosophila epithelia and chick neuroepithelia, but how Dlg1 is localised to the membrane and its importance in mammalian epithelia are unknown. Here we show that Dlg1 is required in non-transformed mammalian epithelial cells for oriented cell divisions, and for normal lumen formation in 3D culture. We demonstrate that CASK, a membrane-associated scaffold, is the factor responsible for Dlg1 membrane localisation during spindle orientation, and thereby identify a new cellular function for CASK. We show that depletion of CASK leads to misoriented divisions in 3D, and to the formation of multilumen structures in cultured kidney and breast epithelial cells. Blocking the direct interaction between CASK and Dlg1 with an interfering peptide disrupts spindle orientation and causes multilumen formation. We further show that the Dlg1-CASK interaction is important for the membrane localisation of the canonical LGN-NuMA complex, required for attachment of the mitotic spindle to the membrane and its correct positioning, as well as for astral microtubule stability. Together these results establish the importance of the CASK-Dlg1 interaction in oriented cell division and epithelial integrity.

Unequal cleavage in leech embryos: zygotic transcription is required for correct spindle orientation in subset of early blastomeres

Development ◽  
1996 ◽  
Vol 122 (2) ◽  
pp. 599-606
Author(s):  
S.T. Bissen ◽  
C.M. Smith
Keyword(s):  
Cell Division ◽  
Early Period ◽  
Spindle Orientation ◽  
Mitotic Spindles ◽  
Maternal Control ◽  
Transcription Analysis ◽  
Cell Divisions ◽  
Zygotic Transcription ◽  
Different Types ◽  
Alpha Amanitin

Leech embryos undergo invariant sequences of equal and unequal cell divisions to give rise to identifiable progeny cells. While many of the early cleavages are under maternal control, the divisions of a subset of early blastomeres (the large cells of the D' lineage) are perturbed after the inhibition of zygotic transcription. Analysis of the different types of cells produced in embryos injected with the transcriptional inhibitor, alpha-amanitin, revealed that the symmetry of cell division is perturbed in these large D'-derived cells during this early period of development. These cells, which would normally undergo a series of equal and unequal cleavages, always undergo equal cleavages after the inhibition of zygotic transcription. It appears that zygotically transcribed gene product(s) are required in the large cells of the D' lineage to orient the mitotic spindles properly for these unequal cell cleavages.

scholarly journals Cell shape and intercellular adhesion regulate mitotic spindle orientation

2019 ◽  
Vol 30 (19) ◽  
pp. 2458-2468 ◽  
Author(s):  
Jingchen Li ◽  
Longcan Cheng ◽  
Hongyuan Jiang
Keyword(s):  
Cell Division ◽  
Epithelial Cells ◽  
Cell Fate ◽  
Cell Shape ◽  
Intercellular Adhesion ◽  
Shape Anisotropy ◽  
Spindle Orientation ◽  
Mitotic Spindles ◽  
Strong Adhesion ◽  
Fate Decision

Cell division orientation plays an essential role in tissue morphogenesis and cell fate decision. Recent studies showed that either cell shape or adhesion geometry can regulate the orientation of mitotic spindles and thereby the cell division orientation. However, how they together regulate the spindle orientation remains largely unclear. In this work, we use a general computational model to investigate the competitive mechanism of determining the spindle orientation between cell shape and intercellular adhesion in epithelial cells. We find the spindle orientation is dominated by the intercellular adhesion when the cell shape anisotropy is small, but dominated by the cell shape when the shape anisotropy is large. A strong adhesion and moderate adhesive size can ensure the planar division of epithelial cells with large apico-basal elongation. We also find the spindle orientation could be perpendicular to the adhesive region when only one side of the cell is adhered to an E-cadherin–coated matrix. But after the cell is compressed, the spindle orientation is governed by the cell shape and the spindle will be parallel to the adhesive region when the cell shape anisotropy is large. Finally, we demonstrate the competition between cell shape and tricellular junctions can also effectively regulate the spindle orientation.

scholarly journals HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Marisa Connell ◽  
Helen Chen ◽  
Jihong Jiang ◽  
Chia-Wei Kuan ◽  
Abbas Fotovati ◽  
...  
Keyword(s):  
Cell Division ◽  
Neural Development ◽  
Cell Types ◽  
Spindle Orientation ◽  
Spindle Positioning ◽  
Over Expression ◽  
Oriented Cell Division ◽  
Neonatal Lethality ◽  
Cortical Localization ◽  
Dependent Pathway

Oriented cell division is one mechanism progenitor cells use during development and to maintain tissue homeostasis. Common to most cell types is the asymmetric establishment and regulation of cortical NuMA-dynein complexes that position the mitotic spindle. Here, we discover that HMMR acts at centrosomes in a PLK1-dependent pathway that locates active Ran and modulates the cortical localization of NuMA-dynein complexes to correct mispositioned spindles. This pathway was discovered through the creation and analysis of Hmmr-knockout mice, which suffer neonatal lethality with defective neural development and pleiotropic phenotypes in multiple tissues. HMMR over-expression in immortalized cancer cells induces phenotypes consistent with an increase in active Ran including defects in spindle orientation. These data identify an essential role for HMMR in the PLK1-dependent regulatory pathway that orients progenitor cell division and supports neural development.

scholarly journals Dlg1 controls planar spindle orientation in the neuroepithelium through direct interaction with LGN

2014 ◽  
Vol 206 (6) ◽  
pp. 707-717 ◽  
Author(s):  
Mehdi Saadaoui ◽  
Mickaël Machicoane ◽  
Florencia di Pietro ◽  
Fred Etoc ◽  
Arnaud Echard ◽  
...  
Keyword(s):  
Mitotic Spindle ◽  
Direct Interaction ◽  
Human Cells ◽  
Spindle Orientation ◽  
Cell Cortex ◽  
Precise Localization ◽  
Cell Divisions ◽  
Evolutionarily Conserved ◽  
Cortical Localization

Oriented cell divisions are necessary for the development of epithelial structures. Mitotic spindle orientation requires the precise localization of force generators at the cell cortex via the evolutionarily conserved LGN complex. However, polarity cues acting upstream of this complex in vivo in the vertebrate epithelia remain unknown. In this paper, we show that Dlg1 is localized at the basolateral cell cortex during mitosis and is necessary for planar spindle orientation in the chick neuroepithelium. Live imaging revealed that Dlg1 is required for directed spindle movements during metaphase. Mechanistically, we show that direct interaction between Dlg1 and LGN promotes cortical localization of the LGN complex. Furthermore, in human cells dividing on adhesive micropatterns, homogenously localized Dlg1 recruited LGN to the mitotic cortex and was also necessary for proper spindle orientation. We propose that Dlg1 acts primarily to recruit LGN to the cortex and that Dlg1 localization may additionally provide instructive cues for spindle orientation.

scholarly journals E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape

2017 ◽  
Vol 114 (29) ◽  
pp. E5845-E5853 ◽  
Author(s):  
Kevin C. Hart ◽  
Jiongyi Tan ◽  
Kathleen A. Siemers ◽  
Joo Yong Sim ◽  
Beth L. Pruitt ◽  
...  
Keyword(s):  
Cell Division ◽  
Cell Monolayer ◽  
Spindle Orientation ◽  
Tissue Cell ◽  
Cellular Behavior ◽  
Cell Monolayers ◽  
Daughter Cells ◽  
Cell Divisions ◽  
Tensile Forces ◽  
E Cadherin

Tissue morphogenesis requires the coordinated regulation of cellular behavior, which includes the orientation of cell division that defines the position of daughter cells in the tissue. Cell division orientation is instructed by biochemical and mechanical signals from the local tissue environment, but how those signals control mitotic spindle orientation is not fully understood. Here, we tested how mechanical tension across an epithelial monolayer is sensed to orient cell divisions. Tension across Madin–Darby canine kidney cell monolayers was increased by a low level of uniaxial stretch, which oriented cell divisions with the stretch axis irrespective of the orientation of the cell long axis. We demonstrate that stretch-induced division orientation required mechanotransduction through E-cadherin cell–cell adhesions. Increased tension on the E-cadherin complex promoted the junctional recruitment of the protein LGN, a core component of the spindle orientation machinery that binds the cytosolic tail of E-cadherin. Consequently, uniaxial stretch triggered a polarized cortical distribution of LGN. Selective disruption of trans engagement of E-cadherin in an otherwise cohesive cell monolayer, or loss of LGN expression, resulted in randomly oriented cell divisions in the presence of uniaxial stretch. Our findings indicate that E-cadherin plays a key role in sensing polarized tensile forces across the tissue and transducing this information to the spindle orientation machinery to align cell divisions.

scholarly journals Epithelial polarity and spindle orientation: intersecting pathways

2013 ◽  
Vol 368 (1629) ◽  
pp. 20130291 ◽  
Author(s):  
Dan T. Bergstralh ◽  
Timm Haack ◽  
Daniel St Johnston
Keyword(s):  
Epithelial Cells ◽  
Cell Fate ◽  
Spindle Orientation ◽  
Mitotic Spindles ◽  
Daughter Cells ◽  
Cell Divisions ◽  
Discs Large ◽  
Stem Cell Divisions ◽  
Fate Determinants ◽  
Cell Fate Determinants

During asymmetric stem cell divisions, the mitotic spindle must be correctly oriented and positioned with respect to the axis of cell polarity to ensure that cell fate determinants are appropriately segregated into only one daughter cell. By contrast, epithelial cells divide symmetrically and orient their mitotic spindles perpendicular to the main apical–basal polarity axis, so that both daughter cells remain within the epithelium. Work in the past 20 years has defined a core ternary complex consisting of Pins, Mud and Gαi that participates in spindle orientation in both asymmetric and symmetric divisions. As additional factors that interact with this complex continue to be identified, a theme has emerged: there is substantial overlap between the mechanisms that orient the spindle and those that establish and maintain apical–basal polarity in epithelial cells. In this review, we examine several factors implicated in both processes, namely Canoe, Bazooka, aPKC and Discs large, and consider the implications of this work on how the spindle is oriented during epithelial cell divisions.

scholarly journals A microtubule-based mechanism predicts cell division orientation in plant embryogenesis

2018 ◽  
Author(s):  
Bandan Chakrabortty ◽  
Viola Willemsen ◽  
Thijs de Zeeuw ◽  
Che-Yang Liao ◽  
Dolf Weijers ◽  
...  
Keyword(s):  
Cell Division ◽  
Cell Walls ◽  
Cell Shape ◽  
Cortical Microtubule ◽  
Minimal Set ◽  
Division Plane ◽  
Plant Morphogenesis ◽  
Cell Divisions ◽  
Microtubule Stability ◽  
Underlying Mechanisms

AbstractOriented cell divisions are significant in plant morphogenesis because plant cells are embedded in cell walls and cannot relocate. Cell divisions follow various regular orientations, but the underlying mechanisms have not been clarified. We show that cell-shape dependent self-organisation of cortical microtubule arrays is crucial for determining planes of early tissue-generating divisions and forms the basis for robust control of cell division orientation in the embryo. To achieve this, we simulate microtubules on actual cell surface shapes from which we derive a minimal set of three rules for proper array orientation. The first rule captures the effects of cell shape alone on microtubule organisation, the second rule describes the regulation of microtubule stability at cell edges and the third rule includes the differential effect of auxin on local microtubule stability. These rules explain early embryonic division plane orientations and offer a framework for understanding patterned cell divisions in plant morphogenesis.

scholarly journals Cadherin Adhesion Receptors Orient the Mitotic Spindle during Symmetric Cell Division in Mammalian Epithelia

2009 ◽  
Vol 20 (16) ◽  
pp. 3740-3750 ◽  
Author(s):  
Nicole den Elzen ◽  
Carmen V. Buttery ◽  
Madhavi P. Maddugoda ◽  
Gang Ren ◽  
Alpha S. Yap
Keyword(s):  
Cell Division ◽  
Asymmetric Cell Division ◽  
Spindle Orientation ◽  
Mitotic Spindles ◽  
Spatial Cues ◽  
Adhesion Receptors ◽  
Interacting Protein ◽  
Division Plane ◽  
Oriented Cell Division ◽  
Tissue Organization

Oriented cell division is a fundamental determinant of tissue organization. Simple epithelia divide symmetrically in the plane of the monolayer to preserve organ structure during epithelial morphogenesis and tissue turnover. For this to occur, mitotic spindles must be stringently oriented in the Z-axis, thereby establishing the perpendicular division plane between daughter cells. Spatial cues are thought to play important roles in spindle orientation, notably during asymmetric cell division. The molecular nature of the cortical cues that guide the spindle during symmetric cell division, however, is poorly understood. Here we show directly for the first time that cadherin adhesion receptors are required for planar spindle orientation in mammalian epithelia. Importantly, spindle orientation was disrupted without affecting tissue cohesion or epithelial polarity. This suggests that cadherin receptors can serve as cues for spindle orientation during symmetric cell division. We further show that disrupting cadherin function perturbed the cortical localization of APC, a microtubule-interacting protein that was required for planar spindle orientation. Together, these findings establish a novel morphogenetic function for cadherin adhesion receptors to guide spindle orientation during symmetric cell division.

Stimulated Virus Production in Vinblastine and Cytochalasin-Induced Multinucleate Cells

1970 ◽  
Vol 28 ◽  
pp. 186-187
Author(s):  
Krishan Awtar
Keyword(s):  
Cell Division ◽  
Normal Cell ◽  
Virus Production ◽  
Multinucleate Cells ◽  
Daughter Cells ◽  
Cell Divisions ◽  
Nuclear Membranes ◽  
Division 2 ◽  
Vinblastine Sulfate

Exposure of cells to low sublethal but mitosis-arresting doses of vinblastine sulfate (Velban) results in the initial arrest of cells in mitosis followed by their subsequent return to an “interphase“-like stage. A large number of these cells reform their nuclear membranes and form large multimicronucleated cells, some containing as many as 25 or more micronuclei (1). Formation of large multinucleate cells is also caused by cytochalasin, by causing the fusion of daughter cells at the end of an otherwise .normal cell division (2). By the repetition of this process through subsequent cell divisions, large cells with 6 or more nuclei are formed.

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