Frizzled regulates localization of cell-fate determinants and mitotic spindle rotation during asymmetric cell division

2000 ◽  
Vol 3 (1) ◽  
pp. 50-57 ◽  
Author(s):  
Yohanns Bellaïche ◽  
Michel Gho ◽  
Julia A. Kaltschmidt ◽  
Andrea H. Brand ◽  
François Schweisguth
Keyword(s):  
Cell Division ◽  
Cell Fate ◽  
Mitotic Spindle ◽  
Asymmetric Cell Division ◽  
Spindle Rotation ◽  
Fate Determinants ◽  
Cell Fate Determinants

scholarly journals Asymmetric cell division during T cell development controls downstream fate

2015 ◽  
Vol 210 (6) ◽  
pp. 933-950 ◽  
Author(s):  
Kim Pham ◽  
Raz Shimoni ◽  
Mirren Charnley ◽  
Mandy J. Ludford-Menting ◽  
Edwin D. Hawkins ◽  
...  
Keyword(s):  
Cell Division ◽  
T Cell ◽  
Cell Fate ◽  
Asymmetric Cell Division ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Clones ◽  
Fate Determinants ◽  
Cell Fate Determinants ◽  
Selection Stage

During mammalian T cell development, the requirement for expansion of many individual T cell clones, rather than merely expansion of the entire T cell population, suggests a possible role for asymmetric cell division (ACD). We show that ACD of developing T cells controls cell fate through differential inheritance of cell fate determinants Numb and α-Adaptin. ACD occurs specifically during the β-selection stage of T cell development, and subsequent divisions are predominantly symmetric. ACD is controlled by interaction with stromal cells and chemokine receptor signaling and uses a conserved network of polarity regulators. The disruption of polarity by deletion of the polarity regulator, Scribble, or the altered inheritance of fate determinants impacts subsequent fate decisions to influence the numbers of DN4 cells arising after the β-selection checkpoint. These findings indicate that ACD enables the thymic microenvironment to orchestrate fate decisions related to differentiation and self-renewal.

scholarly journals Ankle2, A Target of Zika Virus, Controls Asymmetric Cell Division of Neuroblasts and Uncovers a Novel Microcephaly Pathway

2019 ◽  
Author(s):  
N. Link ◽  
H. Chung ◽  
A. Jolly ◽  
M. Withers ◽  
B. Tepe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Nuclear Envelope ◽  
Cell Fate ◽  
Zika Virus ◽  
Asymmetric Cell Division ◽  
Brain Size ◽  
Stem Cell Division ◽  
Fate Determinants ◽  
Cell Fate Determinants

ABSTRACTNeuroblasts in flies divide asymmetrically by establishing polarity, distributing cell fate determinants asymmetrically, and positioning their spindle for cell division. The apical complex contains aPKC, Bazooka (Par3), and Par6, and its activity depends on L(2)gl. We show that Ankle2 interacts with L(2)gl and affects aPKC. Reducing Ankle2 levels disrupts ER and nuclear envelope morphology, releasing the kinase Ballchen/VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par complex localization, and spindle alignment defects. Importantly, removal of one copy ofballchen/VRK1orl(2)glsuppresses the loss ofAnkle2and restores viability and brain size. The Zika virus NS4A protein interacts withDrosophilaAnkle2 and VRK1 in dividing neuroblasts. Human mutational studies implicate this neural cell division pathway in microcephaly and motor neuron disease. In summary, NS4A, ANKLE2, VRK1 and LLGL1 define a novel pathway that impinges on asymmetric determinants of neural stem cell division.

scholarly journals The polarity-induced force imbalance inCaenorhabditis elegansembryos is caused by asymmetric binding rates of dynein to the cortex

2018 ◽  
Vol 29 (26) ◽  
pp. 3093-3104 ◽  
Author(s):  
Ruddi Rodriguez-Garcia ◽  
Laurent Chesneau ◽  
Sylvain Pastezeur ◽  
Julien Roul ◽  
Marc Tramier ◽  
...  
Keyword(s):  
Cell Fate ◽  
Asymmetric Cell Division ◽  
Molecular Motor ◽  
Dependent Manner ◽  
Mitotic Progression ◽  
Posterior Cortex ◽  
Antibody Staining ◽  
Pulling Forces ◽  
Fate Determinants ◽  
Cell Fate Determinants

During asymmetric cell division, the molecular motor dynein generates cortical pulling forces that position the spindle to reflect polarity and adequately distribute cell fate determinants. In Caenorhabditis elegans embryos, despite a measured anteroposterior force imbalance, antibody staining failed to reveal dynein enrichment at the posterior cortex, suggesting a transient localization there. Dynein accumulates at the microtubule plus ends, in an EBP-2EB–dependent manner. This accumulation, although not transporting dynein, contributes modestly to cortical forces. Most dyneins may instead diffuse to the cortex. Tracking of cortical dynein revealed two motions: one directed and the other diffusive-like, corresponding to force-generating events. Surprisingly, while dynein is not polarized at the plus ends or in the cytoplasm, diffusive-like tracks were more frequently found at the embryo posterior tip, where the forces are higher. This asymmetry depends on GPR-1/2LGNand LIN-5NuMA, which are enriched there. In csnk-1(RNAi) embryos, the inverse distribution of these proteins coincides with an increased frequency of diffusive-like tracks anteriorly. Importantly, dynein cortical residence time is always symmetric. We propose that the dynein-binding rate at the posterior cortex is increased, causing the polarity-reflecting force imbalance. This mechanism of control supplements the regulation of mitotic progression through the nonpolarized dynein detachment rate.

scholarly journals Membrane Targeting and Asymmetric Localization of Drosophila Partner of Inscuteable Are Discrete Steps Controlled by Distinct Regions of the Protein

2002 ◽  
Vol 22 (12) ◽  
pp. 4230-4240 ◽  
Author(s):  
Fengwei Yu ◽  
Chin Tong Ong ◽  
William Chia ◽  
Xiaohang Yang
Keyword(s):  
Cell Fate ◽  
Mitotic Spindle ◽  
Protein Localization ◽  
Asymmetric Division ◽  
Terminal Region ◽  
Spindle Orientation ◽  
Functional Domain ◽  
Fate Determinants ◽  
Cell Fate Determinants ◽  
Apical Localization

ABSTRACT Asymmetric division of neural progenitors is a key mechanism by which neuronal diversity in the Drosophila central nervous system is generated. The distinct fates of the daughter cells derived from these divisions are achieved through preferential segregation of the cell fate determinants Prospero and Numb to one of the two daughters. This is achieved by coordinating apical and basal mitotic spindle orientation with the basal cortical localization of the cell fate determinants during mitosis. A complex of apically localized proteins, including Inscuteable (Insc), Partner of Inscuteable (Pins), Bazooka (Baz), DmPar-6, DaPKC, and Gαi, is required to mediate and coordinate basal protein localization with mitotic spindle orientation. Pins, a molecule which directly interacts with Insc, is a key component required for the integrity of this complex; in the absence of Pins, other components become mislocalized or destabilized, and basal protein localization and mitotic spindle orientation are defective. Here we define the functional domains of Pins. We show that the C-terminal region containing the Gαi binding GoLoco motifs is necessary and sufficient for targeting to the neuroblast cortex, which appears to be a prerequisite for apical localization of Pins. The N-terminal tetratricopeptide repeat-containing region of Pins is required for two processes; TPR repeats 1 to 3 plus the C-terminal region are required for apical localization but are insufficient to recruit Insc to the apical cortex, whereas TPR repeats 1 to 7 plus C-terminal Pins can perform both functions. Hence, the abilities of Pins to cortically localize, to apically localize, and to restore Insc apical localization are all separable, and all three capabilities are necessary to mediate asymmetric division. Moreover, the need for N-terminal Pins can be obviated by fusing a minimal Insc functional domain with the C-terminal region of Pins; this chimeric molecule is apically localized and can fulfill the functions of both Insc and Pins.

scholarly journals The endoplasmic reticulum is partitioned asymmetrically during mitosis before cell fate selection in proneuronal cells in the early Drosophila embryo

2017 ◽  
Vol 28 (11) ◽  
pp. 1530-1538 ◽  
Author(s):  
Anthony S. Eritano ◽  
Arturo Altamirano ◽  
Sarah Beyeler ◽  
Norma Gaytan ◽  
Mark Velasquez ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Division ◽  
Cell Fate ◽  
Asymmetric Cell Division ◽  
Asymmetric Division ◽  
Drosophila Embryo ◽  
Early Drosophila Embryo ◽  
Dividing Cells ◽  
Fate Determinants ◽  
Selection Of

Asymmetric cell division is the primary mechanism to generate cellular diversity, and it relies on the correct partitioning of cell fate determinants. However, the mechanism by which these determinants are delivered and positioned is poorly understood, and the upstream signal to initiate asymmetric cell division is unknown. Here we report that the endoplasmic reticulum (ER) is asymmetrically partitioned during mitosis in epithelial cells just before delamination and selection of a proneural cell fate in the early Drosophila embryo. At the start of gastrulation, the ER divides asymmetrically into a population of asynchronously dividing cells at the anterior end of the embryo. We found that this asymmetric division of the ER depends on the highly conserved ER membrane protein Jagunal (Jagn). RNA inhibition of jagn just before the start of gastrulation disrupts this asymmetric division of the ER. In addition, jagn-deficient embryos display defects in apical-basal spindle orientation in delaminated embryonic neuroblasts. Our results describe a model in which an organelle is partitioned asymmetrically in an otherwise symmetrically dividing cell population just upstream of cell fate determination and updates previous models of spindle-based selection of cell fate during mitosis.

An RNA Interference Screen Reveals Fate Determinants Implicated in Asymmetric Cell Division as Potential Regulators of Hematopoietic Stem Cell Self-Renewal

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2462-2462
Author(s):  
Kristin J Hope ◽  
Sonia Cellot ◽  
Stephen Ting ◽  
Guy Sauvageau
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Cell Division ◽  
Rna Interference ◽  
Cell Fate ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Fate Determinants ◽  
Cell Fate Determinants

Abstract During periods of extensive regeneration of the hematopoietic system, hematopoietic stem cells (HSC) undergo largely symmetrical self-renewal divisions, necessary to rapidly replenish the stem cell pool. Under homeostasis, however, it is likely that HSC rely more on asymmetric self-renewal divisions to retain an appropriate number of HSC while still enabling sufficient production of mature blood cells. The unequal partitioning of intrinsic fate determinants underlies the process of asymmetric stem cell division in lower organisms including Drosophila and C. elegans. The tumor suppressive function of specific determinants has been demonstrated in studies where mutation of fate determinants shown to be inhibitory to the self-renewal of one of the two daughter cells generated upon Drosophila neuroblast division, drives exclusive symmetrical stem cell divisions ultimately leading to the formation of larval brain tumors. As HSCs can not yet be definitively prospectively identified, it has been difficult to determine whether a similar segregation of such cell fate determinants underlies the asymmetric/symmetric self-renewal of these cells or whether deregulation of these determinants could also generate hematopoietic malignancies by inducing constitutive symmetric self-renewal divisions. We addressed these questions through a functional genetics approach taking advantage of systematic RNA interference to interrogate the function of polarity factors and cell fate determinants representing candidate HSC self-renewal regulators. From a list of 72 of such factors identified in the literature, 32 murine homologs were selected based on their differentially high level of expression in HSC-enriched populations. For each candidate we generated 3 unique short hairpin RNA (shRNA) encoding retroviral constructs also carrying EGFP for the purposes of following transduced cells. In a primary screen equal numbers of HSC-enriched Lin-CD150+CD48− cells were infected with the library in an arrayed 96-well format yielding an average gene transfer of 60.0 ± 3.2%. The in vivo reconstituting potential was then evaluated in a CRU assay such that identical proportions of each well were transplanted in duplicate. An average of 37.6 ± 5.1% long-term donor reconstitution was demonstrated by luciferase shRNA transduced controls. Directly following infection, the EGFP+ fraction of a portion of each well was separated by FACS to facilitate qRT-PCR determination of knockdown efficiency. Immunophenotypes, cell viability and morphology of well contents cultured an additional 7 days were also assessed. The percent of EGFP− and EGFP+ donor cell contribution was determined by flow cytometric evaluation of peripheral blood samples taken every 4 weeks for a period of 16 weeks. Genes for which shRNA vectors altered late transplant EGFP levels below or above defined thresholds were considered as hits. At present we have identified 4 genes for which shRNA-mediated depletion negatively affects repopulation but does not induce indiscriminate cell death in culture and 1 gene that may act as a self-renewal inhibitor. In one example, two shRNAs directed against the candidate EB3 showed a dramatic loss of EGFP+ cells in vivo. EB3, a member of the microtubule plus-end binding protein family, has previously described roles in the search-and-capture mechanism of spindle positioning. Interestingly, EB1, a closely related family member is also critical in directing the symmetrical as opposed to asymmetrical divisions of primitive neuroepithelial cells in Drosophila. Validation of all identified hits as well as further evaluation of their function through cell cycle, cell death and homing studies is ongoing.

scholarly journals A new role for Notch in the control of polarity and asymmetric cell division of developing T cells

2019 ◽  
Author(s):  
Mirren Charnley ◽  
Mandy Ludford-Menting ◽  
Kim Pham ◽  
Sarah M. Russell
Keyword(s):  
T Cells ◽  
Cell Division ◽  
Cell Fate ◽  
Asymmetric Cell Division ◽  
Single Cells ◽  
Cell Types ◽  
Notch Signalling ◽  
Pass Through ◽  
Fate Determinants ◽  
Different Cell Types

AbstractA fundamental question in biology is how single cells can reliably produce progeny of different cell types. Notch signalling frequently facilitates fate determination. Asymmetric cell division (ACD) often controls segregation of Notch signalling by imposing unequal inheritance of regulators of Notch. Here, we assessed the functional relationship between Notch and ACD in mouse T cell development. To attain immunological specificity, developing T cells must pass through a pivotal stage termed β-selection, which involves Notch signalling and ACD. We assessed functional interactions between Notch and ACD during β-selection using direct presentation of Notch ligands, DL1 and DL4, and pharmacological inhibition of Notch signalling. Contrary to prevailing models, we find Notch controls distribution of Notch1 itself and cell fate determinants, α-Adaptin and Numb. Notch and CXCR4 signalling cooperated to drive polarity during division. Thus, Notch signalling directly orchestrates ACD, and Notch1 is differentially inherited by sibling cells.

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