scholarly journals SRPS associated protein WDR60 regulates the multipolar-to-bipolar transition of migrating neurons during cortical development

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cui Li ◽  
Yu Zheng ◽  
Yufang Zheng ◽  
Zhiheng Xu
Keyword(s):  
Critical Role ◽  
Underlying Mechanism ◽  
Stable Form ◽  
Microtubule Organizing Center ◽  
Microtubule Organization ◽  
Repeat Domain ◽  
Organizing Center ◽  
Newborn Neurons ◽  
And Migration ◽  
Cellular Components

AbstractMutations of WD40 repeat domain 60 (WDR60) have been identified in short-rib polydactyly syndromes (SRPS I–V), a group of lethal congenital disorders characterized by short ribs, polydactyly, and a range of extraskeletal phenotypes. However, the underlying mechanism is still unclear. Here, we report that WDR60 is essential for embryonic development and plays a critical role in the multipolar-bipolar transition and migration of newborn neurons during brain development. Mechanically, we found that WDR60 was located at the microtubule-organizing center to control microtubule organization and possibly, the trafficking of cellular components. Importantly, the migration defect caused by Wdr60 knockdown could be rescued by the stable form of α-Tubulin, α-TubulinK40Q (an acetylation-mimicking mutant). These findings identified a non-cilia function of WDR60 and provided insight into its biological function, as well as the pathogenesis of WDR60 deficiency associated with SRPS.

scholarly journals Phosphoproteomics of CD2 signaling reveals AMPK-dependent regulation of lytic granule polarization in cytotoxic T cells

2020 ◽  
Vol 13 (631) ◽  
pp. eaaz1965 ◽  
Author(s):  
Vanessa Zurli ◽  
Tommaso Montecchi ◽  
Raphael Heilig ◽  
Isabel Poschke ◽  
Michael Volkmar ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic T Cells ◽  
Critical Role ◽  
Underlying Mechanism ◽  
Cell Receptor ◽  
Microtubule Organizing Center ◽  
Lytic Granules ◽  
Organizing Center ◽  
Lytic Granule ◽  
Insight Into

Understanding the costimulatory signaling that enhances the activity of cytotoxic T cells (CTLs) could identify potential targets for immunotherapy. Here, we report that CD2 costimulation plays a critical role in target cell killing by freshly isolated human CD8+ T cells, which represent a challenging but valuable model to gain insight into CTL biology. We found that CD2 stimulation critically enhanced signaling by the T cell receptor in the formation of functional immune synapses by promoting the polarization of lytic granules toward the microtubule-organizing center (MTOC). To gain insight into the underlying mechanism, we explored the CD2 signaling network by phosphoproteomics, which revealed 616 CD2-regulated phosphorylation events in 373 proteins implicated in the regulation of vesicular trafficking, cytoskeletal organization, autophagy, and metabolism. Signaling by the master metabolic regulator AMP-activated protein kinase (AMPK) was a critical node in the CD2 network, which promoted granule polarization toward the MTOC in CD8+ T cells. Granule trafficking was driven by active AMPK enriched on adjacent lysosomes, revealing previously uncharacterized signaling cross-talk between vesicular compartments in CD8+ T cells. Our results thus establish CD2 signaling as key for mediating cytotoxic killing and granule polarization in freshly isolated CD8+ T cells and strengthen the rationale to choose CD2 and AMPK as therapeutic targets to enhance CTL activity.

scholarly journals The Golgi Protein GM130 Regulates Centrosome Morphology and Function

2008 ◽  
Vol 19 (2) ◽  
pp. 745-753 ◽  
Author(s):  
Andrew Kodani ◽  
Christine Sütterlin
Keyword(s):  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Human Cell Lines ◽  
Microtubule Organizing Center ◽  
Microtubule Organization ◽  
Cycle Progression ◽  
Multipolar Spindles ◽  
Organizing Center ◽  
Golgi Protein ◽  
And Function

The Golgi apparatus (GA) of mammalian cells is positioned in the vicinity of the centrosome, the major microtubule organizing center of the cell. The significance of this physical proximity for organelle function and cell cycle progression is only beginning to being understood. We have identified a novel function for the GA protein, GM130, in the regulation of centrosome morphology, position and function during interphase. RNA interference–mediated depletion of GM130 from five human cell lines revealed abnormal interphase centrosomes that were mispositioned and defective with respect to microtubule organization and cell migration. When GM130-depleted cells entered mitosis, they formed multipolar spindles, arrested in metaphase, and died. We also detected aberrant centrosomes during interphase and multipolar spindles during mitosis in ldlG cells, which do not contain detectable GM130. Although GA proteins have been described to regulate mitotic centrosomes and spindle formation, this is the first report of a role for a GA protein in the regulation of centrosomes during interphase.

scholarly journals Kinetics and intermediates of marginal band reformation: evidence for peripheral determinants of microtubule organization.

1984 ◽  
Vol 99 (1) ◽  
pp. 70s-75s ◽  
Author(s):  
M Miller ◽  
F Solomon
Keyword(s):  
Cell Types ◽  
Microtubule Assembly ◽  
Cell Periphery ◽  
Microtubule Organizing Center ◽  
Microtubule Organization ◽  
Mature Erythrocyte ◽  
The Reformation ◽  
Marginal Band ◽  
Organizing Center

The microtubules of the mature erythrocyte of the chicken are confined to a band at the periphery. Whole-mount electron microscopy after extraction reveals that the number of microtubules in each cell is almost the same. All the microtubules can be depolymerized by incubation in the cold, and the marginal band can be quantitatively and qualitatively reformed by return to 39 degrees C. These properties allow the reformation of the marginal band to be treated as an in vivo microtubule assembly reaction. The kinetics of this reaction and the intermediates detected during reformation suggest a mechanism of microtubule organization that is distinct from that observed in other cell types. Apparently only one or two growing microtubule ends are available for assembly--assembly is only detected at the cell periphery, even at early times--and there is no evidence of the participation of a microtubule-organizing center.

scholarly journals Centrosome-dependent microtubule organization sets the conditions for axon formation

2020 ◽  
Author(s):  
Durga Praveen Meka ◽  
Oliver Kobler ◽  
Souhaila Wuesthoff ◽  
Birgit Schwanke ◽  
Christoph Krisp ◽  
...  
Keyword(s):  
Microtubule Dynamics ◽  
Growth Speed ◽  
Microtubule Organizing Center ◽  
Microtubule Organization ◽  
Axon Elongation ◽  
Axon Development ◽  
Organizing Center ◽  
Cytoskeleton Remodeling ◽  
Axon Specification ◽  
Developing Neurons

AbstractMicrotubule remodeling is critical during axon development when the more stable microtubules populate the axon. It is not completely understood, however, how this local cytoskeleton remodeling is coordinated. The centrosome, the main microtubule-organizing center (MTOC), has been suggested to be crucial for axon specification 1–5. Conversely, it was proposed that axon elongation is independent of centrosomal functions 6. Here we report that microtubule dynamics in early neurons follow a radial organization which establishes the conditions for the axon formation. Using high-resolution microscopy of early developing neurons, we demonstrate that few somatic acetylated microtubules are restricted near the centrosome. At later stages, however, acetylated microtubules spread out in the soma and concentrate in the growing axon. Furthermore, live-imaging of the microtubule plus-end binding protein EB3 in early differentiating neurons shows that growing microtubules have increased length and growth speed near the MTOC, suggesting local differences that might favor axon selection. Importantly, due to the lack of somatic stable/acetylated microtubules in early developing neurons, disruption of the F-actin cytoskeleton does not induce multiple axons, as it does at later stages of differentiation. Finally, we demonstrate that overexpression of the centrosomal protein 120 (Cep120), known for promoting microtubule acetylation and stabilization, induces multiple axons, while its downregulation decreases the content of proteins regulating microtubule dynamics and stability, hence hampering axon formation. Collectively, our data show that early centrosome-dependent microtubule organization contributes to axon formation.

scholarly journals NSD3S stabilizes MYC through hindering its interaction with FBXW7

2019 ◽  
Vol 12 (6) ◽  
pp. 438-447 ◽  
Author(s):  
Valentina Gonzalez-Pecchi ◽  
Albert K Kwan ◽  
Sean Doyle ◽  
Andrey A Ivanov ◽  
Yuhong Du ◽  
...  
Keyword(s):  
Critical Role ◽  
Growth Control ◽  
Underlying Mechanism ◽  
Set Domain ◽  
Amino Acid Region ◽  
Binding Interface ◽  
Histone Lysine Methyltransferase ◽  
Repeat Domain ◽  
Lysine Methyltransferase ◽  
Cell Growth Control

Abstract The MYC transcription factor plays a key role in cell growth control. Enhanced MYC protein stability has been found to promote tumorigenesis. Thus, understanding how MYC stability is controlled may have significant implications for revealing MYC-driven growth regulatory mechanisms in physiological and pathological processes. Our previous work identified the histone lysine methyltransferase nuclear receptor binding SET domain protein 3 (NSD3) as a MYC modulator. NSD3S, a noncatalytic isoform of NSD3 with oncogenic activity, appears to bind, stabilize, and activate the transcriptional activity of MYC. However, the mechanism by which NSD3S stabilizes MYC remains to be elucidated. To uncover the nature of the interaction and the underlying mechanism of MYC regulation by NSD3S, we characterized the binding interface between both proteins by narrowing the interface to a 15-amino acid region in NSD3S that is partially required for MYC regulation. Mechanistically, NSD3S binds to MYC and reduces the association of F-box and WD repeat domain containing 7 (FBXW7) with MYC, which results in suppression of FBXW7-mediated proteasomal degradation of MYC and an increase in MYC protein half-life. These results support a critical role for NSD3S in the regulation of MYC function and provide a novel mechanism for NSD3S oncogenic function through inhibition of FBXW7-mediated degradation of MYC.

scholarly journals Fission yeast MOZART1/Mzt1 is an essential γ-tubulin complex component required for complex recruitment to the microtubule organizing center, but not its assembly

2013 ◽  
Vol 24 (18) ◽  
pp. 2894-2906 ◽  
Author(s):  
Hirohisa Masuda ◽  
Risa Mori ◽  
Masashi Yukawa ◽  
Takashi Toda
Keyword(s):  
Fission Yeast ◽  
Spindle Pole Body ◽  
Spindle Pole ◽  
Temperature Sensitive ◽  
Microtubule Organizing Center ◽  
Microtubule Organization ◽  
Unique Role ◽  
Pole Body ◽  
Organizing Center ◽  
Core Components

γ-Tubulin plays a universal role in microtubule nucleation from microtubule organizing centers (MTOCs) such as the animal centrosome and fungal spindle pole body (SPB). γ-Tubulin functions as a multiprotein complex called the γ-tubulin complex (γ-TuC), consisting of GCP1–6 (GCP1 is γ-tubulin). In fungi and flies, it has been shown that GCP1–3 are core components, as they are indispensable for γ-TuC complex assembly and cell division, whereas the other three GCPs are not. Recently a novel conserved component, MOZART1, was identified in humans and plants, but its precise functions remain to be determined. In this paper, we characterize the fission yeast homologue Mzt1, showing that it is essential for cell viability. Mzt1 is present in approximately equal stoichiometry with Alp4/GCP2 and localizes to all the MTOCs, including the SPB and interphase and equatorial MTOCs. Temperature-sensitive mzt1 mutants display varying degrees of compromised microtubule organization, exhibiting multiple defects during both interphase and mitosis. Mzt1 is required for γ-TuC recruitment, but not sufficient to localize to the SPB, which depends on γ-TuC integrity. Intriguingly, the core γ-TuC assembles in the absence of Mzt1. Mzt1 therefore plays a unique role within the γ-TuC components in attachment of this complex to the major MTOC site.

scholarly journals Loss of aMTOCs disrupts spindle pole Aurora A and assembly of the liquid-like meiotic spindle domain (LISD) in oocytes

2021 ◽  
Author(s):  
Xiaotian Wang ◽  
Claudia Baumann ◽  
Rabindranath De La Fuente ◽  
Maria M. Viveiros
Keyword(s):  
Meiotic Division ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Spindle Pole ◽  
Meiotic Spindle ◽  
Aurora A ◽  
Microtubule Organizing Center ◽  
Spindle Poles ◽  
Organizing Center ◽  
Spindle Stability

Oocyte-specific Pericentrin (PCNT) knockdown in transgenic (Tg) mice disrupts acentriolar microtubule organizing center (aMTOC) formation, leading to spindle instability and error-prone meiotic division. Here, we show that PCNT-depleted oocytes lack phosphorylated Aurora A (pAURKA) at spindle poles, while overall levels are unaltered. To test aMTOC-associated AURKA function, MII control (WT) and Tg oocytes were briefly exposed to a specific inhibitor (MLN8237). Similar defects were observed in Tg and MLN8237-treated WT oocytes, including altered spindle structure, increased chromosome misalignment and impaired microtubule regrowth. Yet, AURKA inhibition had a limited effect on Tg oocytes, revealing a critical role for aMTOC-associated AURKA in regulating spindle stability. Notably, spindle instability was associated with disrupted γ-tubulin and lack of the liquid-like meiotic spindle domain (LISD) in Tg oocytes. Analysis of this Tg model provides the first evidence that LISD assembly depends expressly on aMTOC-associated AURKA, and that Ran-mediated spindle formation ensues without the LISD. These data support that loss of aMTOC-associated AURKA and failure of LISD assembly contribute to error-prone meiotic division in PCNT-depleted oocytes, underscoring the essential role of aMTOCs for spindle stability.

scholarly journals PLK1 is required for chromosome compaction and microtubule organization in mouse oocytes

2020 ◽  
Vol 31 (12) ◽  
pp. 1206-1217
Author(s):  
Tara M. Little ◽  
Philip W. Jordan
Keyword(s):  
Chromosome Segregation ◽  
Microtubule Organizing Center ◽  
Microtubule Organization ◽  
Spindle Formation ◽  
Bipolar Spindle ◽  
Mouse Oocytes ◽  
Organizing Center ◽  
Meiosis I

By deleting Plk1 in mouse oocytes before meiotic resumption, we show that PLK1 is essential for the formation of condensed bivalent chromosomes, microtubule organizing center fragmentation, liquid-like spindle domain localization, and bipolar spindle formation. Thus, PLK1 coordinates processes that ensure chromosome segregation during meiosis I.

scholarly journals DUXAP10 inhibition attenuates the proliferation and metastasis of hepatocellular carcinoma cells by regulation of the Wnt/β-catenin and PI3K/Akt signaling pathways

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Kun Han ◽  
Chunqi Li ◽  
Xin Zhang ◽  
Liang Shang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Mapk Pathway ◽  
Critical Role ◽  
Underlying Mechanism ◽  
Mesenchymal Transition ◽  
And Migration ◽  
Therapy Target

AbstractThe long non-coding RNA DUXAP10 has been involved in the development, progression, and metastasis in several human cancers, but its biological function and underlying mechanism in hepatocellular carcinoma (HCC) still undetermined. The present study was proposed to explore the effect of DUXAP10 on the growth and metastasis of HCC cells and the potential mechanisms involved. The results showed that DUXAP10 is dramatically elevated in HCC tumor tissues and cell lines. Knockdown of DUXAP10 by DUXAP10 si-RNA significantly inhibited the cell viability, proliferation and induce the apoptosis of HCC cell line. Meanwhile, inhibition of DUXAP10 attenuates the cell migration, invasion, and epithelial–mesenchymal transition (EMT) process. No significant change of JNK MAPK pathway was detected in DUXAP10 siRNA transfected HCC cell lines. The β-catenin and pAkt levels were decreased in the Hep G2+DUXAP10 siRNA and SMMC7721+DUXAP10 siRNA groups, while the activation of Wnt/β-catenin or PI3K/Akt suppressed the inhibition of DUXAP10 siRNA on cell proliferation and migration. Collectively, DUXAP10 plays a critical role in regulating HCC development, potentially by regulating EMT and cell proliferation through the PI3K/Akt and Wnt/β-catenin signaling. Inhibition of DUXAP10 in HCC HepG2 cells could attenuate the EMT and cell proliferation and invasion. Therefore, DUXAP10 might be a promising therapy target to inhibit the growth of HCC.

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