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Aneuploidy in Human Oocytes and Preimplantation Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
In mitotic cells, spindle formation is driven largely from centrosomes, microtubule organizing centers (MTOC) from which microtubules emanate and capture chromosomes by their kinetochores. However, in many species, oogenesis is acentrosomal, although MTOCs are formed (102). In human oocytes MTOCs are not apparent and the spindle formation is driven by the chromosomes. The first metaphase I takes an astonishing 12–15 hours (83,103) and the spindles are highly unstable (103). Although spindle instability correlates with missegregation, this facet of human oogenesis does not appear to be age-related (103).
Manipulating the Intracellular Trafficking of Nucleic Acids
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Kathleen E. B Meyer, Lisa S. Uyechi, Francis C. Szoka
Microtubules and actin filaments are believed to maintain intracellular distribution of organelles and to facilitate trafficking between organelles (for review see Ref. 62). Microtubules can be viewed as tracks for the movement of organelles and their cargo, where movement is driven by protein motors fueled by ATP (63,64). Microtubules radiate out from the microtubule organizing center (MTOC) into the peripheral regions of the cytoplasm, thus forming an extensive network of fibers throughout the cell (Fig. 2). The fast-growing ends (plus ends) of the microtubule are located at the cell periphery while the slow-growing ends (minus ends) are found at the MTOC. Differential distribution of organelles and transport vesicles are observed in the microtubule network with endosomes found near the plus ends at the cell periphery, whereas Golgi, late endosomes, and lysosomes are clustered near the minus ends near the nucleus.
Endothelial Cell Signaling During Wound Healing
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Data from in vitro models have demonstrated that endothelial wound healing is an integrated process of cell proliferation and cell migration.9 Centrosomes and microtubule organizing centers undergo redistribution,10,11 and both microtubules and microfilaments play important roles in cell spreading and movement during wound closure.11,12 This complex response is modulated by a large array of substances, including growth factors, chemotactic peptides, inflammatory cytokines, and extracellular cations. Insulin-like growth factor 1, platelet-derived growth factor, acidic and basic fibroblast growth factors, and scatter factor (hepatocyte growth factor) all stimulate endothelial cell migratory responses.13–17 Inflammatory cytokines, including interleukins 1, 6, and 8, tumor necrosis factor-α, and transforming growth factor-β, have also been demonstrated to increase endothelial cell motility.18–22 Extracellular magnesium in physiologic concentrations inhibits endothelial motility, whereas abnormally high concentrations are stimulatory.23
SPI2 T3SS effectors facilitate enterocyte apical to basolateral transmigration of Salmonella-containing vacuoles in vivo
Published in Gut Microbes, 2021
Marcus Fulde, Kira van Vorst, Kaiyi Zhang, Alexander J. Westermann, Tobias Busche, Yong Chiun Huei, Katharina Welitschanski, Isabell Froh, Dennis Pägelow, Johanna Plendl, Christiane Pfarrer, Jörn Kalinowski, Jörg Vogel, Peter Valentin-Weigand, Michael Hensel, Karsten Tedin, Urska Repnik, Mathias W. Hornef
Also, the role of the SPI2 T3SS for the positioning of intracellular S. Typhimurium seems to differ between non-polarized cells and polarized enterocytes. In non-polarized cells, SPI2 T3SS effectors were reported to mediate paranuclear localization.6,24,30 In contrast, our findings in highly polarized intestinal epithelial cells in vivo suggest that the interaction of SPI2 T3SS effector molecules with the microtubule network and trafficking machinery facilitates apical to basolateral transmigration. Importantly, this is fully consistent with the different organization of the microtubule network in polarized and non-polarized cells. In non-polarized cells, microtubules extend radially from the microtubule organizing center (MTOC) localized close to the paranuclear Golgi apparatus, whereas in polarized enterocytes they extend from the apical membrane to the basolateral side to facilitate vectoral vesicle transport.32 The continued presence of SPI2 T3SS mutant microcolonies mainly at the apical pole is also reminiscent of the appearance of subapical vesicles in genetic disorders of the intracellular trafficking machinery.33 Thus, the enhanced size and block in apical to basolateral transmigration of SPI2 T3SS mutant and somewhat less pronounced also for SifA mutant SCVs as well as the enhanced size of SseFG and PipB2 deficient S. Typhimurium SCVs suggest a critical role of the SPI2 T3SS and a contribution of the translocated effector molecules SifA, SseFG and PipB2 in the microtubule-mediated transport of the SCV through the epithelial cell in vivo.
Targeting Autophagy In Disease: Recent Advances In Drug Discovery
Published in Expert Opinion on Drug Discovery, 2020
Dasol Kim, Hui-Yun Hwang, Ho Jeong Kwon
In the final maturation/degradation step, autophagosomes traffic toward the microtubule-organizing center (MTOC) to fuse with lysosomes and degrade cargo through lysosomal hydrolases. Two essential processes are pivotal for proper autophagy turnover: (1) autophagosome-lysosome fusion, and (2) lysosomal hydrolase activation. Although the mechanism underlying autophagosome-lysosome fusion is currently unclear, it is under intense investigation. Factors involved in fusion include the endosomal sorting complexes required for transport (ESCRTs), soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE), ultraviolent radiation resistance-associated gene (UVRAG), Rubicon (RUBCN), small GTPase of the Ras-related protein 7 (RAB7), lysosomal associated membrane protein 2 (LAMP2), ion channels, and other tethering factors [13–17]. Because lysosomal enzymes are acid hydrolases (including proteases, glycosidases, nucleases, phosphatases, and lipases) that are active at acidic pH (~5) but not neutral pH, maintaining low pH is essential for ‘active lysosomes’ to induce sequential autophagic turnover. Accordingly, lysosomal ion channel proteins such as vacuolar-type H+-ATPase (V-ATPase) and transient receptor potential mucolipin 1 (TRPML1) play essential roles to maintain lysosomal ionic homeostasis and membrane potential, resulting in lysosome activation by hydrogen cation influx [18].
The role of microtubules in the regulation of epithelial junctions
Published in Tissue Barriers, 2018
Ekaterina Vasileva, Sandra Citi
Among different types of cytoskeletal polymers, microtubules (MTs), along with actin filaments, are the most evolutionarily conserved, since they are present in all eukaryotes, where they promote the generation of mechanical force and movement through kinesin and dynein (for MTs), and myosin (for actin filaments) motors, respectively. Although proteins similar to tubulin and actin are also found in prokaryotes, the associated protein motors appear to be missing.1 MTs are hollow cylindrical polymers of heterodimeric subunits made of α- and β-tubulin, and are typically made up of 13 parallel protofilaments.2 They are polarized, with plus ends, which are highly dynamic, undergoing either rapid polymerization or rapid depolymerization (catastrophe), and minus ends, which are typically either stabilized or acting as sites of depolymerization.3 Polymerizing MTs are nucleated and stabilized at their minus ends by the γ-tubulin ring complex (γ-TuRC). The γ-TuRC is the main structural unit of microtubule organizing centers (MTOCs), which are found both at centrosomes, and at non-centrosomal sites, such as the Golgi apparatus.4 Tubulins are targets for numerous types of post-translational modifications (PTMs) affecting their C-terminal sequences, including de-tyrosination, Δ2-tubulin generation, polyglutamylation, polyglycylation, and acetylation.5 The functional significance and mechanisms of tubulin PTMs have been investigated in neuronal cells, where PTMs regulate MTs organization and interactions with motors, but their role in epithelial cells is less clear.