The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Juergen A Knoblich - One of the best experts on this subject based on the ideXlab platform.
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the par complex and integrins direct Asymmetric Cell Division in adult intestinal stem Cells
Cell Stem Cell, 2012Co-Authors: Spyros Goulas, Ryan Conder, Juergen A KnoblichAbstract:The adult Drosophila midgut is maintained by intestinal stem Cells (ISCs) that generate both self-renewing and differentiating daughter Cells. How this asymmetry is generated is currently unclear. Here, we demonstrate that Asymmetric ISC Division is established by a unique combination of extraCellular and intraCellular polarity mechanisms. We show that Integrin-dependent adhesion to the basement membrane induces Cell-intrinsic polarity and results in the Asymmetric segregation of the Par proteins Par-3, Par-6, and aPKC into the apical daughter Cell. Cell-specific knockdown and overexpression experiments suggest that increased activity of aPKC enhances Delta/Notch signaling in one of the two daughter Cells to induce terminal differentiation. Perturbing this mechanism or altering the orientation of ISC Division results in the formation of intestinal tumors. Our data indicate that mechanisms for intrinsically Asymmetric Cell Division can be adapted to allow for the flexibility in lineage decisions that is required in adult stem Cells.
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Asymmetric Cell Division recent developments and their implications for tumour biology
Nature Reviews Molecular Cell Biology, 2010Co-Authors: Juergen A KnoblichAbstract:The ability of Cells to divide Asymmetrically is essential for generating diverse Cell types during development. The past 10 years have seen tremendous progress in our understanding of this important biological process. We have learned that localized phosphorylation events are responsible for the Asymmetric segregation of Cell fate determinants in mitosis and that centrosomes and microtubules play important parts in this process. The relevance of Asymmetric Cell Division for stem Cell biology has added a new dimension to the field, and exciting connections between Asymmetric Cell Division and tumorigenesis have begun to emerge.
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dividing Cellular asymmetry Asymmetric Cell Division and its implications for stem Cells and cancer
Genes & Development, 2009Co-Authors: Ralph A Neumuller, Juergen A KnoblichAbstract:Cell Division is commonly thought to involve the equal distribution of Cellular components into the two daughter Cells. During many Cell Divisions, however, proteins, membrane compartments, organelles, or even DNA are Asymmetrically distributed between the two daughter Cells. Here, we review the various types of asymmetries that have been described in yeast and in animal Cells. Asymmetric segregation of protein determinants is particularly relevant for stem Cell biology. We summarize the relevance of Asymmetric Cell Divisions in various stem Cell systems and discuss why defects in Asymmetric Cell Division can lead to the formation of tumors.
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directional delta and notch trafficking in sara endosomes during Asymmetric Cell Division
Nature, 2009Co-Authors: F. Coumailleau, Maximilian Fürthauer, Juergen A Knoblich, Marcos GonzalezgaitanAbstract:In Drosophila melanogaster, the sensory organ precursor Cells (SOP) undergo Asymmetric Division resulting in a posterior pIIa Cell and an anterior pIIb Cell that further divide to create daughters with different Cell fates. SOP Division is dependent on signalling by the transmembrane receptor Notch and its receptor, Delta. Notch and Delta are expressed in pIIa and pIIb Cells, but Notch signalling is activated only in the pIIa Cell. In this study, Coumailleau et al. provide a mechanistic basis for differential signalling of Notch. They show that in SOP, Notch and Delta traffic to special endosomes marked by the protein SARA. During Cell Division, these endosomes move to the central spindle and are then Asymmetrically segregated into the pIIa Cell where Notch signalling is activated. Hence Asymmetric trafficking of Notch/Delta containing endosomes increases Notch signalling in pIIa Cells and decreasing it in pIIb Cells. This study provides a mechanistic basis for differential signalling of Notch, by showing that in fly sensory organ precursors, Notch and Delta traffic to special endosomes marked by the protein Sara. The Asymmetric trafficking of endosomes containing Notch and Delta increases Notch signalling in pIIa daughter Cells and decreases it in pIIb Cells. Endocytosis has a crucial role during Notch signalling after the Asymmetric Division of fly sensory organ precursors (SOPs): directional signalling is mediated by differential endocytosis of the ligand Delta and the Notch effector Sanpodo in one of the SOP daughters, pIIb1,2,3. Here we show a new mechanism of directional signalling on the basis of the trafficking of Delta and Notch molecules already internalized in the SOP and subsequently targeted to the other daughter Cell, pIIa. Internalized Delta and Notch traffic to an endosome marked by the protein Sara4,5. During SOP mitosis, Sara endosomes containing Notch and Delta move to the central spindle and then to pIIa. Subsequently, in pIIa (but not in pIIb) Notch appears cleaved in Sara endosomes in a γ-secretase- and Delta internalization-dependent manner, indicating that the release of the intraCellular Notch tail to activate Notch target genes has occurred. We thus uncover a new mechanism to bias signalling even before Asymmetric endocytosis of Sanpodo and Delta takes place in the daughter Cells: already during SOP mitosis, Asymmetric targeting of Delta and Notch-containing Sara endosomes will increase Notch signalling in pIIa and decrease it in pIIb.
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Directional Delta and Notch trafficking in Sara endosomes during Asymmetric Cell Division
Nature, 2009Co-Authors: F. Coumailleau, Maximilian Fürthauer, Juergen A Knoblich, Marcos González-gaitánAbstract:Endocytosis has a crucial role during Notch signalling after the Asymmetric Division of fly sensory organ precursors (SOPs): directional signalling is mediated by differential endocytosis of the ligand Delta and the Notch effector Sanpodo in one of the SOP daughters, pIIb. Here we show a new mechanism of directional signalling on the basis of the trafficking of Delta and Notch molecules already internalized in the SOP and subsequently targeted to the other daughter Cell, pIIa. Internalized Delta and Notch traffic to an endosome marked by the protein Sara. During SOP mitosis, Sara endosomes containing Notch and Delta move to the central spindle and then to pIIa. Subsequently, in pIIa (but not in pIIb) Notch appears cleaved in Sara endosomes in a gamma-secretase- and Delta internalization-dependent manner, indicating that the release of the intraCellular Notch tail to activate Notch target genes has occurred. We thus uncover a new mechanism to bias signalling even before Asymmetric endocytosis of Sanpodo and Delta takes place in the daughter Cells: already during SOP mitosis, Asymmetric targeting of Delta and Notch-containing Sara endosomes will increase Notch signalling in pIIa and decrease it in pIIb.
Jeff W M Bulte - One of the best experts on this subject based on the ideXlab platform.
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applicability and limitations of mr tracking of neural stem Cells with Asymmetric Cell Division and rapid turnover the case of the shiverer dysmyelinated mouse brain
Magnetic Resonance in Medicine, 2007Co-Authors: Piotr Walczak, Dorota A Kedziorek, Assaf A Gilad, Brad P Barnett, Jeff W M BulteAbstract:LacZ-transfected C17.2 neural stem Cells (NSCs) were labeled with the superparamagnetic iron oxide formulation Feridex prior to ICV injection in shi/shi neonates. Feridex labeling did not alter Cell differentiation in vitro and in vivo. Initially, MR images obtained at 11.7T correlated closely to NSC distribution as assessed with anti-dextran and anti-beta-galactosidase double-fluorescent immunostaining. However, at 6 days postgrafting there was already a pronounced mismatch between the hypointense MR signal and the histologically determined Cell distribution, with a surprisingly sharp cutoff rather than a gradual decrease of signal. Positive in vivo BrdU labeling of NSCs showed that significant Cell replication occurred post-transplantation, causing rapid dilution of Feridex particles between mother and daughter Cells toward undetectable levels. Neural differentiation experiments demonstrated Asymmetric Cell Division, explaining the observed sharp cutoff. At later time points (2 weeks), the mismatch further increased by the presence of non-Cell-associated Feridex particles resulting from active excretion or Cell death. These results are a first demonstration of the inability of MRI to track rapidly dividing and self-renewing, Asymmetrically dividing SCs. Therefore, MR Cell tracking should only be applied for nonproliferating Cells or short-term monitoring of highly-proliferative Cells, with mitotic symmetry or asymmetry being important for determining its applicability.
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applicability and limitations of mr tracking of neural stem Cells with Asymmetric Cell Division and rapid turnover the case of the shiverer dysmyelinated mouse brain
Magnetic Resonance in Medicine, 2007Co-Authors: Piotr Walczak, Dorota A Kedziorek, Assaf A Gilad, Brad P Barnett, Jeff W M BulteAbstract:LacZ-transfected C17.2 neural stem Cells (NSCs) were labeled with the superparamagnetic iron oxide formulation Feridex prior to ICV injection in shi/shi neonates. Feridex labeling did not alter Cell differentiation in vitro and in vivo. Initially, MR images obtained at 11.7T correlated closely to NSC distribution as assessed with anti-dextran and anti-β-galactosidase double-fluorescent immunostaining. However, at 6 days postgrafting there was already a pronounced mismatch between the hypointense MR signal and the histologically determined Cell distribution, with a surprisingly sharp cutoff rather than a gradual decrease of signal. Positive in vivo BrdU labeling of NSCs showed that significant Cell replication occurred post-transplantation, causing rapid dilution of Feridex particles between mother and daughter Cells toward undetectable levels. Neural differentiation experiments demonstrated Asymmetric Cell Division, explaining the observed sharp cutoff. At later time points (2 weeks), the mismatch further increased by the presence of non-Cell-associated Feridex particles resulting from active excretion or Cell death. These results are a first demonstration of the inability of MRI to track rapidly dividing and self-renewing, Asymmetrically dividing SCs. Therefore, MR Cell tracking should only be applied for nonproliferating Cells or short-term monitoring of highly-proliferative Cells, with mitotic symmetry or asymmetry being important for determining its applicability. Magn Reson Med 58:261–269, 2007. © 2007 Wiley-Liss, Inc.
Yukiko M. Yamashita - One of the best experts on this subject based on the ideXlab platform.
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Emerging mechanisms of Asymmetric stem Cell Division
The Journal of cell biology, 2018Co-Authors: Zsolt G Venkei, Yukiko M. YamashitaAbstract:The Asymmetric Cell Division of stem Cells, which produces one stem Cell and one differentiating Cell, has emerged as a mechanism to balance stem Cell self-renewal and differentiation. Elaborate Cellular mechanisms that orchestrate the processes required for Asymmetric Cell Divisions are often shared between stem Cells and other Asymmetrically dividing Cells. During Asymmetric Cell Division, Cells must establish asymmetry/polarity, which is guided by varying degrees of intrinsic versus extrinsic cues, and use intraCellular machineries to divide in a desired orientation in the context of the asymmetry/polarity. Recent studies have expanded our knowledge on the mechanisms of Asymmetric Cell Divisions, revealing the previously unappreciated complexity in setting up the Cellular and/or environmental asymmetry, ensuring binary outcomes of the fate determination. In this review, we summarize recent progress in understanding the mechanisms and regulations of Asymmetric stem Cell Division.
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the centrosome orientation checkpoint is germline stem Cell specific and operates prior to the spindle assembly checkpoint in drosophila testis
Development, 2015Co-Authors: Zsolt Venkei, Yukiko M. YamashitaAbstract:Asymmetric Cell Division is utilized by a broad range of Cell types to generate two daughter Cells with distinct Cell fates. In stem Cell populations Asymmetric Cell Division is believed to be crucial for maintaining tissue homeostasis, failure of which can lead to tissue degeneration or hyperplasia/tumorigenesis. Asymmetric Cell Divisions also underlie Cell fate diversification during development. Accordingly, the mechanisms by which Asymmetric Cell Division is achieved have been extensively studied, although the check points that are in place to protect against potential perturbation of the process are poorly understood. Drosophila melanogaster male germline stem Cells (GSCs) possess a checkpoint, termed the centrosome orientation checkpoint (COC), that monitors correct centrosome orientation with respect to the component Cells of the niche to ensure Asymmetric stem Cell Division. To our knowledge, the COC is the only checkpoint mechanism identified to date that specializes in monitoring the orientation of Cell Division in multiCellular organisms. Here, by establishing colcemid-induced microtubule depolymerization as a sensitive assay, we examined the characteristics of COC activity and find that it functions uniquely in GSCs but not in their differentiating progeny. We show that the COC operates in the G2 phase of the Cell cycle, independently of the spindle assembly checkpoint. This study may provide a framework for identifying and understanding similar mechanisms that might be in place in other Asymmetrically dividing Cell types.
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Asymmetric stem Cell Division precision for robustness
Cell Stem Cell, 2012Co-Authors: Mayu Inaba, Yukiko M. YamashitaAbstract:Asymmetric Cell Division (ACD) produces two daughter Cells with distinct fates or characteristics. Many adult stem Cells use ACD as a means of maintaining stem Cell number and thus tissue homeostasis. Here, we review recent progress on ACD, discussing conservation between stem and non-stem Cell systems, molecular mechanisms, and the biological meaning of ACD.
Marcos Gonzalezgaitan - One of the best experts on this subject based on the ideXlab platform.
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polarized endosome dynamics by spindle asymmetry during Asymmetric Cell Division
Nature, 2015Co-Authors: Emmanuel Derivery, Carole Seum, Alicia Daeden, Sylvain Loubery, Laurent Holtzer, Frank Julicher, Marcos GonzalezgaitanAbstract:During Asymmetric Division, fate determinants at the Cell cortex segregate unequally into the two daughter Cells. It has recently been shown that Sara (Smad anchor for receptor activation) signalling endosomes in the cytoplasm also segregate Asymmetrically during Asymmetric Division. Biased dispatch of Sara endosomes mediates Asymmetric Notch/Delta signalling during the Asymmetric Division of sensory organ precursors in Drosophila. In flies, this has been generalized to stem Cells in the gut and the central nervous system, and, in zebrafish, to neural precursors of the spinal cord. However, the mechanism of Asymmetric endosome segregation is not understood. Here we show that the plus-end kinesin motor Klp98A targets Sara endosomes to the central spindle, where they move bidirectionally on an antiparallel array of microtubules. The microtubule depolymerizing kinesin Klp10A and its antagonist Patronin generate central spindle asymmetry. This Asymmetric spindle, in turn, polarizes endosome motility, ultimately causing Asymmetric endosome dispatch into one daughter Cell. We demonstrate this mechanism by inverting the polarity of the central spindle by polar targeting of Patronin using nanobodies (single-domain antibodies). This spindle inversion targets the endosomes to the wrong Cell. Our data uncover the molecular and physical mechanism by which organelles localized away from the Cellular cortex can be dispatched Asymmetrically during Asymmetric Division.
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directional delta and notch trafficking in sara endosomes during Asymmetric Cell Division
Nature, 2009Co-Authors: F. Coumailleau, Maximilian Fürthauer, Juergen A Knoblich, Marcos GonzalezgaitanAbstract:In Drosophila melanogaster, the sensory organ precursor Cells (SOP) undergo Asymmetric Division resulting in a posterior pIIa Cell and an anterior pIIb Cell that further divide to create daughters with different Cell fates. SOP Division is dependent on signalling by the transmembrane receptor Notch and its receptor, Delta. Notch and Delta are expressed in pIIa and pIIb Cells, but Notch signalling is activated only in the pIIa Cell. In this study, Coumailleau et al. provide a mechanistic basis for differential signalling of Notch. They show that in SOP, Notch and Delta traffic to special endosomes marked by the protein SARA. During Cell Division, these endosomes move to the central spindle and are then Asymmetrically segregated into the pIIa Cell where Notch signalling is activated. Hence Asymmetric trafficking of Notch/Delta containing endosomes increases Notch signalling in pIIa Cells and decreasing it in pIIb Cells. This study provides a mechanistic basis for differential signalling of Notch, by showing that in fly sensory organ precursors, Notch and Delta traffic to special endosomes marked by the protein Sara. The Asymmetric trafficking of endosomes containing Notch and Delta increases Notch signalling in pIIa daughter Cells and decreases it in pIIb Cells. Endocytosis has a crucial role during Notch signalling after the Asymmetric Division of fly sensory organ precursors (SOPs): directional signalling is mediated by differential endocytosis of the ligand Delta and the Notch effector Sanpodo in one of the SOP daughters, pIIb1,2,3. Here we show a new mechanism of directional signalling on the basis of the trafficking of Delta and Notch molecules already internalized in the SOP and subsequently targeted to the other daughter Cell, pIIa. Internalized Delta and Notch traffic to an endosome marked by the protein Sara4,5. During SOP mitosis, Sara endosomes containing Notch and Delta move to the central spindle and then to pIIa. Subsequently, in pIIa (but not in pIIb) Notch appears cleaved in Sara endosomes in a γ-secretase- and Delta internalization-dependent manner, indicating that the release of the intraCellular Notch tail to activate Notch target genes has occurred. We thus uncover a new mechanism to bias signalling even before Asymmetric endocytosis of Sanpodo and Delta takes place in the daughter Cells: already during SOP mitosis, Asymmetric targeting of Delta and Notch-containing Sara endosomes will increase Notch signalling in pIIa and decrease it in pIIb.
Pierre Gonczy - One of the best experts on this subject based on the ideXlab platform.
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structural determinants underlying the temperature sensitive nature of a gα mutant in Asymmetric Cell Division of caenorhabditis elegans
Journal of Biological Chemistry, 2008Co-Authors: Christopher A Johnston, Pierre Gonczy, Katayoun Afshar, Jason T Snyder, Gregory G Tall, David P Siderovski, Francis S WillardAbstract:Heterotrimeric G-proteins are integral to a conserved regulatory module that influences metazoan Asymmetric Cell Division (ACD). In the Caenorhabditis elegans zygote, GOA-1 (Gαo) and GPA-16 (Gαi) are involved in generating forces that pull on astral microtubules and position the spindle Asymmetrically. GPA-16 function has been analyzed in vivo owing notably to a temperature-sensitive allele gpa-16(it143), which, at the restrictive temperature, results in spindle orientation defects in early embryos. Here we identify the structural basis of gpa-16(it143), which encodes a point mutation (G202D) in the switch II region of GPA-16. Using Gαi1(G202D) as a model in biochemical analyses, we demonstrate that high temperature induces instability of the mutant Gα. At the permissive temperature, the mutant Gα was stable upon GTP binding, but switch II rearrangement was compromised, as were activation state-selective interactions with regulators involved in ACD, including GoLoco motifs, RGS proteins, and RIC-8. We solved the crystal structure of the mutant Gα bound to GDP, which indicates a unique switch II conformation as well as steric constraints that suggest activated GPA-16(it143) is destabilized relative to wild type. Spindle severing in gpa-16(it143) embryos revealed that pulling forces are symmetric and markedly diminished at the restrictive temperature. Interestingly, pulling forces are Asymmetric and generally similar in magnitude to wild type at the permissive temperature despite defects in the structure of GPA-16(it143). These normal pulling forces in gpa-16(it143) embryos at the permissive temperature were attributable to GOA-1 function, underscoring a complex interplay of Gα subunit function in ACD.
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mechanisms of Asymmetric Cell Division flies and worms pave the way
Nature Reviews Molecular Cell Biology, 2008Co-Authors: Pierre GonczyAbstract:Asymmetric Cell Division, which occurs when a mother Cell gives rise to two daughter Cells with different fates, is crucial for generating diversity during development and for the function of stem Cells. Studies in flies and worms have provided important advances for understanding this process. Asymmetric Cell Division is fundamental for generating diversity in multiCellular organisms. The mechanisms that govern Asymmetric Cell Division are increasingly well understood, owing notably to studies that were conducted in Drosophila melanogaster and Caenorhabditis elegans. Lessons learned from these two model organisms also apply to Cells that divide Asymmetrically in other metazoans, such as self-renewing stem Cells in mammals.
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mechanisms of Asymmetric Cell Division flies and worms pave the way
Nature Reviews Molecular Cell Biology, 2008Co-Authors: Pierre GonczyAbstract:Asymmetric Cell Division is fundamental for generating diversity in multiCellular organisms. The mechanisms that govern Asymmetric Cell Division are increasingly well understood, owing notably to studies that were conducted in Drosophila melanogaster and Caenorhabditis elegans. Lessons learned from these two model organisms also apply to Cells that divide Asymmetrically in other metazoans, such as self-renewing stem Cells in mammals.
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Asymmetric Cell Division and axis formation in the embryo
Wormbook, 2005Co-Authors: Pierre Gonczy, Lesilee S RoseAbstract:: Asymmetric Cell Divisions play an important role in generating diversity during metazoan development. In the early C. elegans embryo, a series of Asymmetric Divisions are crucial for establishing the three principal axes of the body plan (AP, DV, LR) and for segregating determinants that specify Cell fates. In this review, we focus on events in the one-Cell embryo that result in the establishment of the AP axis and the first Asymmetric Division. We first describe how the sperm-derived centrosome initiates movements of the cortical actomyosin network that result in the polarized distribution of PAR proteins. We then briefly discuss how components acting downstream of the PAR proteins mediate unequal segregation of Cell fate determinants to the anterior blastomere AB and the posterior blastomere P1. We also review how a heterotrimeric G protein pathway generates cortically based pulling forces acting on astral microtubules, thus mediating centrosome and spindle positioning in response to AP polarity cues. In addition, we briefly highlight events involved in establishing the DV and LR axes. The DV axis is established at the four-Cell stage, following specific Cell-Cell interactions that occur between P2 and EMS, the two daughters of P1, as well as between P2 and ABp, a daughter of AB. The LR axis is established shortly thereafter by the Division pattern of ABa and ABp. We conclude by mentioning how findings made in early C. elegans embryos are relevant to understanding Asymmetric Cell Division and pattern formation across metazoan evolution.
