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.

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 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.

The Histone Acetyltransferase CBP Is Essential for Conventional T Cell Development.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2294-2294
Author(s):  
Tomofusa Fukuyama ◽  
Fayçal Boussouar ◽  
Lawryn H. Kasper ◽  
Jan M. van Deursen ◽  
Paul K. Brindle
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Chemokine Receptors ◽  
Fas Ligand ◽  
T Cell Development ◽  
Cell Development ◽  
Mutant Mice ◽  
Effector Memory ◽  
Creb Binding Protein ◽  
Cell Fate Decisions

Abstract Defining the epigenetic mechanisms (e.g. chromatin modifications) that underlie T cell fate decisions is a major challenge. The transcriptional coactivators CREB binding protein (CBP) and the closely related p300 comprise a two-member family of histone/protein acetyltransferases that interact with over 50 T lymphocyte-essential transcriptional regulators. Rather than having distinct regulatory roles, CBP and p300 are often thought to confer utilitarian transactivation and histone modifying functions to transcription factors that mediate T cell fate. In contrast to this view, we show here that CBP acts uniquely in conventional T cell development. Inactivation of CBP, but not p300, starting at the double negative stage of T cell development yielded thymocytes with partial activation of an effector/memory- or innate-T cell program. CD8SP thymocytes from CBP mutant mice expressed genes that define professional CD8 cells such as Il-2/Il-15 receptor β chain, granzyme A, interferon γ (Ifnγ), Fas ligand, perforin, and the chemokine receptors Ccr5, and Cxcr3. CD4SP thymocytes from CBP mutant mice also expressed effector genes such as Ifnγ, Il-4, and Ccr5. In addition, CD8SP and CD4SP thymocytes from CBP mutant mice produced Ifnγ protein when the cells were stimulated with phorbol ester and ionomycin. Mechanistically, loss of CBP acted cell non-autonomously to induce the expression of the CD8 T cell master regulatory transcription factor eomesodermin (Eomes). This suggests that CBP in thymocytes or T cells controls an extracellular factor that helps demarcate conventional naïve T cell development in the thymus from effector/memory T cell differentiation in the periphery.

scholarly journals Multiple extrathymic precursors contribute to T-cell development with different kinetics

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1137-1144 ◽  
Author(s):  
Namita Saran ◽  
Marcin Łyszkiewicz ◽  
Jens Pommerencke ◽  
Katrin Witzlau ◽  
Ramin Vakilzadeh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Precursor ◽  
Lineage Differentiation ◽  
Multipotent Cells ◽  
Kinetics Of

Abstract T-cell development in the thymus depends on continuous supply of T-cell progenitors from bone marrow (BM). Several extrathymic candidate progenitors have been described that range from multipotent cells to lymphoid cell committed progenitors and even largely T-lineage committed precursors. However, the nature of precursors seeding the thymus under physiologic conditions has remained largely elusive and it is not known whether there is only one physiologic T-cell precursor population or many. Here, we used a competitive in vivo assay based on depletion rather than enrichment of classes of BM-derived precursor populations, thereby only minimally altering physiologic precursor ratios to assess the contribution of various extrathymic precursors to T-lineage differentiation. We found that under these conditions multiple precursors, belonging to both multipotent progenitor (MPP) and common lymphoid progenitor (CLP) subsets have robust T-lineage potential. However, differentiation kinetics of different precursors varied considerably, which might ensure continuous thymic output despite gated importation of extrathymic precursors. In conclusion, our data suggest that the thymus functions to impose T-cell fate on any precursor capable of filling the limited number of progenitor niches.

Notch Activation Converts B Cells into a T Cell Fate at the Earliest Stages of B Cell Committed Progenitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3151-3151
Author(s):  
Jalal Taneera ◽  
Emma Smith ◽  
Mikael Sigvardsson ◽  
Emil Hansson ◽  
Urban Lindahl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Stage ◽  
Cell Commitment ◽  
Notch Activation

Abstract Notch activation has been suggested to promote T cell development at the expense of B cell commitment at the level of a common lymphoid progenitor prior to B cell commitment. Here, we explored the possibility that Notch activation might be able to switch the fate of already committed B cell progenitors towards T cell development upon Notch activation. To address this we overexpressed constitutively activated Notch-3 (N3IC) in B cell progenitors purified from transgenic mice in which human CD25 is expressed under control of the λ5 promoter. Strikingly, whereas untransduced and control transduced B220+λ5+CD3− B cell progenitors gave rise exclusively to B cells, CD4+ and CD8+ T cells but no B cells were derived from N3IC-transduced cells when transplanted into sublethally irradiated NOD-SCID mice. Gene expression profiling demonstrated that untransduced B220+ λ5+CD3− B cell progenitors expressed λ5 and CD19 but not the T cell specific genes GATA-3, lck and pTα, whereas CD3+ T cells derived from N3IC-transduced B220+λ5+CD3−cells failed to express λ5 and CD19, but were positive for GATA-3, lck and pTα expression as well as a and b T cell rearrangement. Furthermore, DJ rearrangements were detected at very low levels in CD3+ cells isolated from normal non-transduced BM, but were more abundant in the N3IC-transduced CD3+ BM cells. Noteworthy, N3IC-transduced B220+λ5+CD3−CD19+ proB cell progenitors failed to generate B as well as T cells, whereas N3IC-transduced B220+λ5+CD3−CD19− pre-proB cells produced exclusively T cells, even when evaluated at low cell numbers. In conclusion Notch activation can switch committed B cell progenitors from a B cell to a T cell fate, but this plasticity is lost at the Pro-B cell stage, upon upregulation of CD19 expression.

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.

Cell-fate decisions in early T cell development: regulation by cytokine receptors and the pre-TCR

1999 ◽  
Vol 11 (1) ◽  
pp. 23-37 ◽  
Author(s):  
Mariëlle C. Haks ◽  
Mariëtte A. Oosterwegel ◽  
Bianca Blom ◽  
Hergen M. Spits ◽  
Ada M Kruisbeek
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
Cytokine Receptors ◽  
Cell Fate Decisions ◽  
Development Regulation
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