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The Microtubule Cytoskeleton in Chromosome Segregation and Beyond

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Motility and Adhesion".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 52696
Because of the COVID-19, we extended the submission deadline to 30 June 2020. If you want to contribute to this Special Issue but still need more time, please feel free to contact us.

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Special Issue Editors

Dr. Vladimir Joukov

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Guest Editor

N.N. Petrov National Medical Research Center of Oncology, 197758 Saint-Petersburg, Russia
Interests: cell division; spindle assembly; centrosome biogenesis; protein homeostasis; tumor suppression; regeneration; angiogenesis

Prof. Dr. Masamitsu Sato

E-Mail Website
Guest Editor

Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan
Interests: cell division; cell differentiation; meiosis; mitosis; gene expression; nucleus; chromosome segregation; cytoskeleton; microtubules

Special Issue Information

Dear Colleagues,

Faithful chromosome segregation during cell division is accomplished by a highly sophisticated molecular machine termed the mitotic (or meiotic) spindle. The spindle is composed of microtubules, polar, dynamic filaments formed by polymerization of alpha- and beta-tubulin heterodimers. New microtubules are generated and organized at centrosomes and other structures collectively called microtubule-organizing centers. Defects in spindle assembly and positioning may lead to cell death or genomic abnormalities—the underlying causes of diseases, such as developmental disorders and cancer.

In interphase and postmitotic cells, the microtubule-nucleating capacity of centrosomes is usually attenuated and reassigned to other sites, as a means to achieve the microtubule cytoskeleton architecture best suited for the needs of each particular cell type. Microtubules form an intracellular scaffold that helps to maintain cell shape and act as tracks along which motor proteins transport a variety of cargo to different cellular compartments. Emerging evidence suggests that microtubule assembly in quiescent and differentiated cells involves certain spindle assembly proteins (or their paralogs) and may require the activity of mitotic protein kinases.

Owing to its indispensable role in cell division and in various cellular processes, the microtubule cytoskeleton is an attractive therapeutic target. Indeed, the microtubule-targeting agents are among the most effective drugs used in cancer chemotherapy and also show great promise for treating neurodegenerative disorders. By contrast, clinical application of antimitotic drugs, such as inhibitors of mitotic kinases, has been less successful, for reasons yet unknown. Comprehensive knowledge of how the microtubule cytoskeleton is formed and functions in dividing and quiescent cells may substantially advance our understanding of disease pathogenesis and help develop new effective treatments. We hope this Special Issue of Cells will be a step towards achieving this goal. We invite your contributions, either in the form of original research articles, short communications, or reviews, related to the following topics:

Mitotic and meiotic spindle assembly in various eukaryotes;
Chromosome segregation;
Centrosomal and noncentrosomal microtubule-organizing centers;
Microtubule nucleation, dynamics, and organization;
Spindle positioning and cell polarity;
The interplay between the microtubule and actin cytoskeletons;
Microtubule cytoskeleton remodeling during cell differentiation;
Mitotic surveillance mechanisms;
Regulation of microtubule cytoskeleton by disease-related proteins;
Mechanisms of action of microtubule-targeting and antimitotic agents.

Dr. Vladimir Joukov
Prof. Masamitsu Sato
Guest Editors

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Keywords

Microtubule cytoskeleton
Spindle assembly
Chromosome segregation
Microtubule-targeting agents

Published Papers (10 papers)

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Research

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27 pages, 15156 KiB

Open AccessFeature PaperArticle

Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation

by Charoula Peta, Emmanouella Tsirimonaki, Dimitris Samouil, Kyriaki Georgiadou and Dimitra Mangoura

Cells 2020, 9(11), 2348; https://doi.org/10.3390/cells9112348 - 23 Oct 2020

Cited by 5 | Viewed by 3559

Abstract

Mitotic spindles are highly organized, microtubule (MT)-based, transient structures that serve the fundamental function of unerring chromosome segregation during cell division and thus of genomic stability during tissue morphogenesis and homeostasis. Hence, a multitude of MT-associated proteins (MAPs) regulates the dynamic assembly of MTs in preparation for mitosis. Some tumor suppressors, normally functioning to prevent tumor development, have now emerged as significant MAPs. Among those, neurofibromin, the product of the Neurofibromatosis-1 gene (NF1), a major Ras GTPase activating protein (RasGAP) in neural cells, controls also the critical function of chromosome congression in astrocytic cellular contexts. Cell type- and development-regulated splicings may lead to the inclusion or exclusion of NF1exon51, which bears a nuclear localization sequence (NLS) for nuclear import at G2; yet the functions of the produced NLS and ΔNLS neurofibromin isoforms have not been previously addressed. By using a lentiviral shRNA system, we have generated glioblastoma SF268 cell lines with conditional knockdown of NLS or ΔNLS transcripts. In dissecting the roles of NLS or ΔNLS neurofibromins, we found that NLS-neurofibromin knockdown led to increased density of cytosolic MTs but loss of MT intersections, anastral spindles featuring large hollows and abnormal chromosome positioning, and finally abnormal chromosome segregation and increased micronuclei frequency. Therefore, we propose that NLS neurofibromin isoforms exert prominent mitotic functions. Full article

(This article belongs to the Special Issue The Microtubule Cytoskeleton in Chromosome Segregation and Beyond)

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24 pages, 4848 KiB

Open AccessArticle

The Spindle Assembly Checkpoint Functions during Early Development in Non-Chordate Embryos

by Janet Chenevert, Marianne Roca, Lydia Besnardeau, Antonella Ruggiero, Dalileh Nabi, Alex McDougall, Richard R. Copley, Elisabeth Christians and Stefania Castagnetti

Cells 2020, 9(5), 1087; https://doi.org/10.3390/cells9051087 - 28 Apr 2020

Cited by 9 | Viewed by 3854

Abstract

In eukaryotic cells, a spindle assembly checkpoint (SAC) ensures accurate chromosome segregation, by monitoring proper attachment of chromosomes to spindle microtubules and delaying mitotic progression if connections are erroneous or absent. The SAC is thought to be relaxed during early embryonic development. Here, we evaluate the checkpoint response to lack of kinetochore-spindle microtubule interactions in early embryos of diverse animal species. Our analysis shows that there are two classes of embryos, either proficient or deficient for SAC activation during cleavage. Sea urchins, mussels, and jellyfish embryos show a prolonged delay in mitotic progression in the absence of spindle microtubules from the first cleavage division, while ascidian and amphioxus embryos, like those of Xenopus and zebrafish, continue mitotic cycling without delay. SAC competence during early development shows no correlation with cell size, chromosome number, or kinetochore to cell volume ratio. We show that SAC proteins Mad1, Mad2, and Mps1 lack the ability to recognize unattached kinetochores in ascidian embryos, indicating that SAC signaling is not diluted but rather actively silenced during early chordate development. Full article

(This article belongs to the Special Issue The Microtubule Cytoskeleton in Chromosome Segregation and Beyond)

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14 pages, 2149 KiB

Open AccessFeature PaperArticle

Tubulin Resists Degradation by Cereblon-Recruiting PROTACs

by Ivana Gasic, Brian J. Groendyke, Radosław P. Nowak, J. Christine Yuan, Joann Kalabathula, Eric S. Fischer, Nathanael S. Gray and Timothy J. Mitchison

Cells 2020, 9(5), 1083; https://doi.org/10.3390/cells9051083 - 27 Apr 2020

Cited by 19 | Viewed by 7898

Abstract

Dysregulation of microtubules and tubulin homeostasis has been linked to developmental disorders, neurodegenerative diseases, and cancer. In general, both microtubule-stabilizing and destabilizing agents have been powerful tools for studies of microtubule cytoskeleton and as clinical agents in oncology. However, many cancers develop resistance to these agents, limiting their utility. We sought to address this by developing a different kind of agent: tubulin-targeted small molecule degraders. Degraders (also known as proteolysis-targeting chimeras (PROTACs)) are compounds that recruit endogenous E3 ligases to a target of interest, resulting in the target’s degradation. We developed and examined several series of α- and β-tubulin degraders, based on microtubule-destabilizing agents. Our results indicate, that although previously reported covalent tubulin binders led to tubulin degradation, in our hands, cereblon-recruiting PROTACs were not efficient. In summary, while we consider tubulin degraders to be valuable tools for studying the biology of tubulin homeostasis, it remains to be seen whether the PROTAC strategy can be applied to this target of high clinical relevance. Full article

(This article belongs to the Special Issue The Microtubule Cytoskeleton in Chromosome Segregation and Beyond)

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21 pages, 6974 KiB

Open AccessArticle

Excess TPX2 Interferes with Microtubule Disassembly and Nuclei Reformation at Mitotic Exit

by Francesco D. Naso, Valentina Sterbini, Elena Crecca, Italia A. Asteriti, Alessandra D. Russo, Maria Giubettini, Enrico Cundari, Catherine Lindon, Alessandro Rosa and Giulia Guarguaglini

Cells 2020, 9(2), 374; https://doi.org/10.3390/cells9020374 - 06 Feb 2020

Cited by 15 | Viewed by 4943

Abstract

The microtubule-associated protein TPX2 is a key mitotic regulator that contributes through distinct pathways to spindle assembly. A well-characterised function of TPX2 is the activation, stabilisation and spindle localisation of the Aurora-A kinase. High levels of TPX2 are reported in tumours and the effects of its overexpression have been investigated in cancer cell lines, while little is known in non-transformed cells. Here we studied TPX2 overexpression in hTERT RPE-1 cells, using either the full length TPX2 or a truncated form unable to bind Aurora-A, to identify effects that are dependent—or independent—on its interaction with the kinase. We observe significant defects in mitotic spindle assembly and progression through mitosis that are more severe when overexpressed TPX2 is able to interact with Aurora-A. Furthermore, we describe a peculiar, and Aurora-A-interaction-independent, phenotype in telophase cells, with aberrantly stable microtubules interfering with nuclear reconstitution and the assembly of a continuous lamin B1 network, resulting in daughter cells displaying doughnut-shaped nuclei. Our results using non-transformed cells thus reveal a previously uncharacterised consequence of abnormally high TPX2 levels on the correct microtubule cytoskeleton remodelling and G1 nuclei reformation, at the mitosis-to-interphase transition. Full article

(This article belongs to the Special Issue The Microtubule Cytoskeleton in Chromosome Segregation and Beyond)

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Review

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25 pages, 3047 KiB

Open AccessFeature PaperReview

Mechanical Mechanisms of Chromosome Segregation

by Maya I. Anjur-Dietrich, Colm P. Kelleher and Daniel J. Needleman

Cells 2021, 10(2), 465; https://doi.org/10.3390/cells10020465 - 22 Feb 2021

Cited by 16 | Viewed by 4827

Abstract

Chromosome segregation—the partitioning of genetic material into two daughter cells—is one of the most crucial processes in cell division. In all Eukaryotes, chromosome segregation is driven by the spindle, a microtubule-based, self-organizing subcellular structure. Extensive research performed over the past 150 years has identified numerous commonalities and contrasts between spindles in different systems. In this review, we use simple coarse-grained models to organize and integrate previous studies of chromosome segregation. We discuss sites of force generation in spindles and fundamental mechanical principles that any understanding of chromosome segregation must be based upon. We argue that conserved sites of force generation may interact differently in different spindles, leading to distinct mechanical mechanisms of chromosome segregation. We suggest experiments to determine which mechanical mechanism is operative in a particular spindle under study. Finally, we propose that combining biophysical experiments, coarse-grained theories, and evolutionary genetics will be a productive approach to enhance our understanding of chromosome segregation in the future. Full article

(This article belongs to the Special Issue The Microtubule Cytoskeleton in Chromosome Segregation and Beyond)

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29 pages, 1671 KiB

Open AccessFeature PaperReview

Microtubule Organization in Striated Muscle Cells

by Robert Becker, Marina Leone and Felix B. Engel

Cells 2020, 9(6), 1395; https://doi.org/10.3390/cells9061395 - 03 Jun 2020

Cited by 35 | Viewed by 8348

Abstract

Distinctly organized microtubule networks contribute to the function of differentiated cell types such as neurons, epithelial cells, skeletal myotubes, and cardiomyocytes. In striated (i.e., skeletal and cardiac) muscle cells, the nuclear envelope acts as the dominant microtubule-organizing center (MTOC) and the function of the centrosome—the canonical MTOC of mammalian cells—is attenuated, a common feature of differentiated cell types. We summarize the mechanisms known to underlie MTOC formation at the nuclear envelope, discuss the significance of the nuclear envelope MTOC for muscle function and cell cycle progression, and outline potential mechanisms of centrosome attenuation. Full article

(This article belongs to the Special Issue The Microtubule Cytoskeleton in Chromosome Segregation and Beyond)

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18 pages, 3300 KiB

Open AccessReview

How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter

by Masashi Yukawa, Yasuhiro Teratani and Takashi Toda

Cells 2020, 9(5), 1154; https://doi.org/10.3390/cells9051154 - 07 May 2020

Cited by 10 | Viewed by 4260

Abstract

The bipolar mitotic spindle drives accurate chromosome segregation by capturing the kinetochore and pulling each set of sister chromatids to the opposite poles. In this review, we describe recent findings on the multiple pathways leading to bipolar spindle formation in fission yeast and discuss these results from a broader perspective. The roles of three mitotic kinesins (Kinesin-5, Kinesin-6 and Kinesin-14) in spindle assembly are depicted, and how a group of microtubule-associated proteins, sister chromatid cohesion and the kinetochore collaborate with these motors is shown. We have paid special attention to the molecular pathways that render otherwise essential Kinesin-5 to become non-essential: how cells build bipolar mitotic spindles without the need for Kinesin-5 and where the alternate forces come from are considered. We highlight the force balance for bipolar spindle assembly and explain how outward and inward forces are generated by various ways, in which the proper fine-tuning of microtubule dynamics plays a crucial role. Overall, these new pathways have illuminated the remarkable plasticity and adaptability of spindle mechanics. Kinesin molecules are regarded as prospective targets for cancer chemotherapy and many specific inhibitors have been developed. However, several hurdles have arisen against their clinical implementation. This review provides insight into possible strategies to overcome these challenges. Full article

(This article belongs to the Special Issue The Microtubule Cytoskeleton in Chromosome Segregation and Beyond)

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14 pages, 895 KiB

Open AccessFeature PaperReview

Hyaluronan Mediated Motility Receptor (HMMR) Encodes an Evolutionarily Conserved Homeostasis, Mitosis, and Meiosis Regulator Rather than a Hyaluronan Receptor

by Zhengcheng He, Lin Mei, Marisa Connell and Christopher A. Maxwell

Cells 2020, 9(4), 819; https://doi.org/10.3390/cells9040819 - 28 Mar 2020

Cited by 47 | Viewed by 5903

Abstract

Hyaluronan is an extracellular matrix component that absorbs water in tissues and engages cell surface receptors, like Cluster of Differentiation 44 (CD44), to promote cellular growth and movement. Consequently, CD44 demarks stem cells in normal tissues and tumor-initiating cells isolated from neoplastic tissues. Hyaluronan mediated motility receptor (HMMR, also known as RHAMM) is another one of few defined hyaluronan receptors. HMMR is also associated with neoplastic processes and its role in cancer progression is often attributed to hyaluronan-mediated signaling. But, HMMR is an intracellular, microtubule-associated, spindle assembly factor that localizes protein complexes to augment the activities of mitotic kinases, like polo-like kinase 1 and Aurora kinase A, and control dynein and kinesin motor activities. Expression of HMMR is elevated in cells prior to and during mitosis and tissues with detectable HMMR expression tend to be highly proliferative, including neoplastic tissues. Moreover, HMMR is a breast cancer susceptibility gene product. Here, we briefly review the associations between HMMR and tumorigenesis as well as the structure and evolution of HMMR, which identifies Hmmr-like gene products in several insect species that do not produce hyaluronan. This review supports the designation of HMMR as a homeostasis, mitosis, and meiosis regulator, and clarifies how its dysfunction may promote the tumorigenic process and cancer progression. Full article

(This article belongs to the Special Issue The Microtubule Cytoskeleton in Chromosome Segregation and Beyond)

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22 pages, 2872 KiB

Open AccessReview

Microtubule-Associated Proteins with Regulatory Functions by Day and Pathological Potency at Night

by Judit Oláh, Attila Lehotzky, Sándor Szunyogh, Tibor Szénási, Ferenc Orosz and Judit Ovádi

Cells 2020, 9(2), 357; https://doi.org/10.3390/cells9020357 - 04 Feb 2020

Cited by 18 | Viewed by 3748

Abstract

The sensing, integrating, and coordinating features of the eukaryotic cells are achieved by the complex ultrastructural arrays and multifarious functions of the cytoskeleton, including the microtubule network. Microtubules play crucial roles achieved by their decoration with proteins/enzymes as well as by posttranslational modifications. This review focuses on the Tubulin Polymerization Promoting Protein (TPPP/p25), a new microtubule associated protein, on its “regulatory functions by day and pathological functions at night”. Physiologically, the moonlighting TPPP/p25 modulates the dynamics and stability of the microtubule network by bundling microtubules and enhancing the tubulin acetylation due to the inhibition of tubulin deacetylases. The optimal endogenous TPPP/p25 level is crucial for its physiological functions, to the differentiation of oligodendrocytes, which are the major constituents of the myelin sheath. Pathologically, TPPP/p25 forms toxic oligomers/aggregates with α-synuclein in neurons and oligodendrocytes in Parkinson’s disease and Multiple System Atrophy, respectively; and their complex is a potential therapeutic drug target. TPPP/p25-derived microtubule hyperacetylation counteracts uncontrolled cell division. All these issues reveal the anti-mitotic and α-synuclein aggregation-promoting potency of TPPP/p25, consistent with the finding that Parkinson’s disease patients have reduced risk for certain cancers. Full article

(This article belongs to the Special Issue The Microtubule Cytoskeleton in Chromosome Segregation and Beyond)

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Other

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13 pages, 5046 KiB

Open AccessPerspective

Digital Spindle: A New Way to Explore Mitotic Functions by Whole Cell Data Collection and a Computational Approach

by Norio Yamashita, Masahiko Morita, Hideo Yokota and Yuko Mimori-Kiyosue

Cells 2020, 9(5), 1255; https://doi.org/10.3390/cells9051255 - 19 May 2020

Cited by 4 | Viewed by 4257

Abstract

From cells to organisms, every living system is three-dimensional (3D), but the performance of fluorescence microscopy has been largely limited when attempting to obtain an overview of systems’ dynamic processes in three dimensions. Recently, advanced light-sheet illumination technologies, allowing drastic improvement in spatial discrimination, volumetric imaging times, and phototoxicity/photobleaching, have been making live imaging to collect precise and reliable 3D information increasingly feasible. In particular, lattice light-sheet microscopy (LLSM), using an ultrathin light-sheet, enables whole-cell 3D live imaging of cellular processes, including mitosis, at unprecedented spatiotemporal resolution for extended periods of time. This technology produces immense and complex data, including a significant amount of information, raising new challenges for big image data analysis and new possibilities for data utilization. Once the data are digitally archived in a computer, the data can be reused for various purposes by anyone at any time. Such an information science approach has the potential to revolutionize the use of bioimage data, and provides an alternative method for cell biology research in a data-driven manner. In this article, we introduce examples of analyzing digital mitotic spindles and discuss future perspectives in cell biology. Full article

(This article belongs to the Special Issue The Microtubule Cytoskeleton in Chromosome Segregation and Beyond)

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