scholarly journals Thirty years of search and capture: The complex simplicity of mitotic spindle assembly

2015 ◽  
Vol 211 (6) ◽  
pp. 1103-1111 ◽  
Author(s):  
Rebecca Heald ◽  
Alexey Khodjakov
Keyword(s):  
Cell Division ◽  
Mitotic Spindle ◽  
Spindle Assembly ◽  
Microtubule Dynamics ◽  
Adaptive Changes ◽  
Bipolar Spindle ◽  
Chromosome Architecture ◽  
Self Assembling ◽  
Motor Activities ◽  
Mitotic Spindle Assembly

Cell division is enacted by a microtubule-based, self-assembling macromolecular machine known as the mitotic spindle. In 1986, Kirschner and Mitchison proposed that by undergoing dynamic cycles of growth and disassembly, microtubules search for chromosomes. Capture of microtubules by the kinetochores progressively connects chromosomes to the bipolar spindle. 30 years later, “search and capture” remains the cornerstone of spindle assembly. However, a variety of facilitating mechanisms such as regulation of microtubule dynamics by diffusible gradients, spatially selective motor activities, and adaptive changes in chromosome architecture have been discovered. We discuss how these mechanisms ensure that the spindle assembles rapidly and with a minimal number of errors.

scholarly journals Nup98 regulates bipolar spindle assembly through association with microtubules and opposition of MCAK

2011 ◽  
Vol 22 (5) ◽  
pp. 661-672 ◽  
Author(s):  
Marie K. Cross ◽  
Maureen A. Powers
Keyword(s):  
Nuclear Pore Complex ◽  
Mitotic Spindle ◽  
Spindle Assembly ◽  
Microtubule Dynamics ◽  
Nuclear Pore ◽  
Bipolar Spindle ◽  
Terminal Domain ◽  
C Terminus ◽  
Mitotic Spindle Assembly

During mitosis, the nuclear pore complex is disassembled and, increasingly, nucleoporins are proving to have mitotic functions when released from the pore. We find a contribution of the nucleoporin Nup98 to mitotic spindle assembly through regulation of microtubule dynamics. When added to Xenopus extract spindle assembly assays, the C-terminal domain of Nup98 stimulates uncontrolled growth of microtubules. Conversely, inhibition or depletion of Nup98 leads to formation of stable monopolar spindles. Spindle bipolarity is restored by addition of purified, recombinant Nup98 C-terminus. The minimal required region of Nup98 corresponds to a portion of the C-terminal domain lacking a previously characterized function. We show association between this region of the C-terminus of Nup98 and both Taxol-stabilized microtubules and the microtubule-depolymerizing mitotic centromere–associated kinesin (MCAK). Importantly, we demonstrate that this domain of Nup98 inhibits MCAK depolymerization activity in vitro. These data support a model in which Nup98 interacts with microtubules and antagonizes MCAK activity, thus promoting bipolar spindle assembly.

scholarly journals Mechanisms of chromosome biorientation and bipolar spindle assembly analyzed by computational modeling

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Christopher Edelmaier ◽  
Adam R Lamson ◽  
Zachary R Gergely ◽  
Saad Ansari ◽  
Robert Blackwell ◽  
...  
Keyword(s):  
Mitotic Spindle ◽  
Spindle Assembly ◽  
Extensive Study ◽  
Bipolar Spindle ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
Length Regulation ◽  
Mitotic Spindle Assembly ◽  
Early Mitosis ◽  
Segregation Of Chromosomes

The essential functions required for mitotic spindle assembly and chromosome biorientation and segregation are not fully understood, despite extensive study. To illuminate the combinations of ingredients most important to align and segregate chromosomes and simultaneously assemble a bipolar spindle, we developed a computational model of fission-yeast mitosis. Robust chromosome biorientation requires progressive restriction of attachment geometry, destabilization of misaligned attachments, and attachment force dependence. Large spindle length fluctuations can occur when the kinetochore-microtubule attachment lifetime is long. The primary spindle force generators are kinesin-5 motors and crosslinkers in early mitosis, while interkinetochore stretch becomes important after biorientation. The same mechanisms that contribute to persistent biorientation lead to segregation of chromosomes to the poles after anaphase onset. This model therefore provides a framework to interrogate key requirements for robust chromosome biorientation, spindle length regulation, and force generation in the spindle.

scholarly journals Mechanisms of chromosome biorientation and bipolar spindle assembly analyzed by computational modeling

2019 ◽  
Author(s):  
Christopher J. Edelmaier ◽  
Adam R. Lamson ◽  
Zachary R. Gergely ◽  
Saad Ansari ◽  
Robert Blackwell ◽  
...  
Keyword(s):  
Mitotic Spindle ◽  
Spindle Assembly ◽  
Extensive Study ◽  
Bipolar Spindle ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
Length Regulation ◽  
Mitotic Spindle Assembly ◽  
Early Mitosis ◽  
Segregation Of Chromosomes

AbstractThe essential functions required for mitotic spindle assembly and chromosome biorientation and segregation are not fully understood, despite extensive study. To illuminate the combinations of ingredients most important to align and segregate chromosomes and simultaneously assemble a bipolar spindle, we developed a computational model of fission-yeast mitosis. Robust chromosome biorientation requires progressive restriction of attachment geometry, destabilization of misaligned attachments, and attachment force dependence. Large spindle length fluctuations can occur when the kinetochore-microtubule attachment lifetime is long. The primary spindle force generators are kinesin-5 motors and crosslinkers in early mitosis, while interkinetochore stretch becomes important after biorientation. The same mechanisms that contribute to persistent biorientation lead to segregation of chromosomes to the poles after anaphase onset. This model therefore provides a framework to interrogate key requirements for robust chromosome biorientation, spindle length regulation, and force generation in the spindle.

scholarly journals Microtubule pivoting enables mitotic spindle assembly in S. cerevisiae

2021 ◽  
Vol 220 (3) ◽  
Author(s):  
Kimberly K. Fong ◽  
Trisha N. Davis ◽  
Charles L. Asbury
Keyword(s):  
Mitotic Spindle ◽  
Spindle Assembly ◽  
Force Generation ◽  
Initial Contact ◽  
Bipolar Spindle ◽  
Spindle Poles ◽  
Mitotic Spindle Assembly ◽  
Spindle Microtubules ◽  
Pole Component

To assemble a bipolar spindle, microtubules emanating from two poles must bundle into an antiparallel midzone, where plus end–directed motors generate outward pushing forces to drive pole separation. Midzone cross-linkers and motors display only modest preferences for antiparallel filaments, and duplicated poles are initially tethered together, an arrangement that instead favors parallel interactions. Pivoting of microtubules around spindle poles might help overcome this geometric bias, but the intrinsic pivoting flexibility of the microtubule–pole interface has not been directly measured, nor has its importance during early spindle assembly been tested. By measuring the pivoting of microtubules around isolated yeast spindle poles, we show that pivoting flexibility can be modified by mutating a microtubule-anchoring pole component, Spc110. By engineering mutants with different flexibilities, we establish the importance of pivoting in vivo for timely pole separation. Our results suggest that passive thermal pivoting can bring microtubules from side-by-side poles into initial contact, but active minus end–directed force generation will be needed to achieve antiparallel alignment.

scholarly journals Human Ovarian Granulosa Cells Isolated during an IVF Procedure Exhibit Differential Expression of Genes Regulating Cell Division and Mitotic Spindle Formation

2019 ◽  
Vol 8 (12) ◽  
pp. 2026
Author(s):  
Maciej Brązert ◽  
Wiesława Kranc ◽  
Błażej Chermuła ◽  
Katarzyna Kowalska ◽  
Maurycy Jankowski ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Granulosa Cells ◽  
Mitotic Spindle ◽  
Spindle Assembly ◽  
In Vitro Cultivation ◽  
Cellular Ultrastructure ◽  
Mitotic Spindle Assembly

Granulosa cells (GCs) are a population of somatic cells whose role after ovulation is progesterone production. GCs were collected from patients undergoing controlled ovarian stimulation during an in vitro fertilization procedure, and they were maintained for 1, 7, 15, and 30 days of in vitro primary culture before collection for further gene expression analysis. A study of genes involved in the biological processes of interest was carried out using expression microarrays. To validate the obtained results, Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR) was performed. The direction of changes in the expression of the selected genes was confirmed in most of the examples. Six ontological groups (“cell cycle arrest”, “cell cycle process”, “mitotic spindle organization”, “mitotic spindle assembly checkpoint”, “mitotic spindle assembly”, and “mitotic spindle checkpoint”) were analyzed in this study. The results of the microarrays obtained by us allowed us to identify two groups of genes whose expressions were the most upregulated (FAM64A, ANLN, TOP2A, CTGF, CEP55, BIRC5, PRC1, DLGAP5, GAS6, and NDRG1) and the most downregulated (EREG, PID1, INHA, RHOU, CXCL8, SEPT6, EPGN, RDX, WNT5A, and EZH2) during the culture. The cellular ultrastructure showed the presence of structures characteristic of mitotic cell division: a centrosome surrounded by a pericentric matrix, a microtubule system, and a mitotic spindle connected to chromosomes. The main goal of the study was to identify the genes involved in mitotic division and to identify the cellular ultrastructure of GCs in a long-term in vitro culture. All of the genes in these groups were subjected to downstream analysis, and their function and relation to the ovarian environment are discussed. The obtained results suggest that long-term in vitro cultivation of GCs may lead to their differentiation toward another cell type, including cells with cancer-like characteristics.

scholarly journals Theory of cytoskeletal reorganization during crosslinker-mediated mitotic spindle assembly

2018 ◽  
Author(s):  
A. R. Lamson ◽  
C. J. Edelmaier ◽  
M. A. Glaser ◽  
M. D. Betterton
Keyword(s):  
Mitotic Spindle ◽  
Large Scale ◽  
Dynamic Instability ◽  
Kinetic Monte Carlo ◽  
Spindle Assembly ◽  
Spindle Pole ◽  
Balance Model ◽  
Cytoskeletal Reorganization ◽  
Bipolar Spindle ◽  
Mitotic Spindle Assembly

AbstractCells grow, move, and respond to outside stimuli by large-scale cytoskeletal reorganization. A prototypical example of cytoskeletal remodeling is mitotic spindle assembly, during which micro-tubules nucleate, undergo dynamic instability, bundle, and organize into a bipolar spindle. Key mechanisms of this process include regulated filament polymerization, crosslinking, and motor-protein activity. Remarkably, using passive crosslinkers, fission yeast can assemble a bipolar spindle in the absence of motor proteins. We develop a torque-balance model that describes this reorganization due to dynamic microtubule bundles, spindle-pole bodies, the nuclear envelope, and passive crosslinkers to predict spindle-assembly dynamics. We compare these results to those obtained with kinetic Monte Carlo-Brownian dynamics simulations, which include crosslinker-binding kinetics and other stochastic effects. Our results show that rapid crosslinker reorganization to microtubule overlaps facilitates crosslinker-driven spindle assembly, a testable prediction for future experiments. Combining these two modeling techniques, we illustrate a general method for studying cytoskeletal network reorganization.

scholarly journals Pharmacologic inhibition of CDC25 phosphatases impairs interphase microtubule dynamics and mitotic spindle assembly

2007 ◽  
Vol 6 (1) ◽  
pp. 318-325 ◽  
Author(s):  
Martine Cazales ◽  
Rose Boutros ◽  
Marie-Christine Brezak ◽  
Sophie Chaumeron ◽  
Grégoire Prevost ◽  
...  
Keyword(s):  
Mitotic Spindle ◽  
Spindle Assembly ◽  
Microtubule Dynamics ◽  
Mitotic Spindle Assembly ◽  
Pharmacologic Inhibition
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