Special Issue "Mechanisms of Mitotic Chromosome Segregation"

A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (1 October 2016)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Guest Editor
Prof. Dr. J. Richard McIntosh

Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309-0347, USA
Website | E-Mail
Interests: Mechanisms of mitotic chromosome motion, microtubule dynamics, spindle structure, motor enzymes, force generation by microtubule dynamics

Special Issue Information

Dear Colleagues,

This volume focuses on the mechanisms by which a mitotic spindle interact with a replicated genome to assure its accurate segregation to daughter cells at the time of cell division. The following subjects are treated by world-renown specialists: 1) Foundations of modern research on mitotic mechanisms; 2) Kinetochore structure; 3) Kinetochore assembly and function; 4) Spindle assembly; 5) Spindle assembly in plant cells; 6) Chromosome congression to the metaphase plate; 7) The spindle assembly checkpoint; 8) Correcting mitotic errors; 9) Anaphase A; 10) Anaphase B.

Prof. Dr. J. Richard McIntosh
Guest Editor

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Keywords

  • mitosis
  • chromosome segregation
  • mitotic spindle
  • microtubule
  • kinetochore
  • centrosome
  • spindle assembly checkpoint
  • anaphase
  • motor enzyme
  • kinesin
  • dynein
  • microtubule dynamics

Published Papers (10 papers)

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Review

Open AccessReview Anaphase A: Disassembling Microtubules Move Chromosomes toward Spindle Poles
Biology 2017, 6(1), 15; doi:10.3390/biology6010015
Received: 30 December 2016 / Revised: 4 February 2017 / Accepted: 10 February 2017 / Published: 17 February 2017
Cited by 1 | PDF Full-text (4196 KB) | HTML Full-text | XML Full-text
Abstract
The separation of sister chromatids during anaphase is the culmination of mitosis and one of the most strikingly beautiful examples of cellular movement. It consists of two distinct processes: Anaphase A, the movement of chromosomes toward spindle poles via shortening of the connecting
[...] Read more.
The separation of sister chromatids during anaphase is the culmination of mitosis and one of the most strikingly beautiful examples of cellular movement. It consists of two distinct processes: Anaphase A, the movement of chromosomes toward spindle poles via shortening of the connecting fibers, and anaphase B, separation of the two poles from one another via spindle elongation. I focus here on anaphase A chromosome-to-pole movement. The chapter begins by summarizing classical observations of chromosome movements, which support the current understanding of anaphase mechanisms. Live cell fluorescence microscopy studies showed that poleward chromosome movement is associated with disassembly of the kinetochore-attached microtubule fibers that link chromosomes to poles. Microtubule-marking techniques established that kinetochore-fiber disassembly often occurs through loss of tubulin subunits from the kinetochore-attached plus ends. In addition, kinetochore-fiber disassembly in many cells occurs partly through ‘flux’, where the microtubules flow continuously toward the poles and tubulin subunits are lost from minus ends. Molecular mechanistic models for how load-bearing attachments are maintained to disassembling microtubule ends, and how the forces are generated to drive these disassembly-coupled movements, are discussed. Full article
(This article belongs to the Special Issue Mechanisms of Mitotic Chromosome Segregation) Printed Edition available
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Open AccessReview Mechanisms of Chromosome Congression during Mitosis
Biology 2017, 6(1), 13; doi:10.3390/biology6010013
Received: 1 October 2016 / Revised: 7 January 2017 / Accepted: 28 January 2017 / Published: 17 February 2017
Cited by 2 | PDF Full-text (3964 KB) | HTML Full-text | XML Full-text
Abstract
Chromosome congression during prometaphase culminates with the establishment of a metaphase plate, a hallmark of mitosis in metazoans. Classical views resulting from more than 100 years of research on this topic have attempted to explain chromosome congression based on the balance between opposing
[...] Read more.
Chromosome congression during prometaphase culminates with the establishment of a metaphase plate, a hallmark of mitosis in metazoans. Classical views resulting from more than 100 years of research on this topic have attempted to explain chromosome congression based on the balance between opposing pulling and/or pushing forces that reach an equilibrium near the spindle equator. However, in mammalian cells, chromosome bi-orientation and force balance at kinetochores are not required for chromosome congression, whereas the mechanisms of chromosome congression are not necessarily involved in the maintenance of chromosome alignment after congression. Thus, chromosome congression and maintenance of alignment are determined by different principles. Moreover, it is now clear that not all chromosomes use the same mechanism for congressing to the spindle equator. Those chromosomes that are favorably positioned between both poles when the nuclear envelope breaks down use the so-called “direct congression” pathway in which chromosomes align after bi-orientation and the establishment of end-on kinetochore-microtubule attachments. This favors the balanced action of kinetochore pulling forces and polar ejection forces along chromosome arms that drive chromosome oscillatory movements during and after congression. The other pathway, which we call “peripheral congression”, is independent of end-on kinetochore microtubule-attachments and relies on the dominant and coordinated action of the kinetochore motors Dynein and Centromere Protein E (CENP-E) that mediate the lateral transport of peripheral chromosomes along microtubules, first towards the poles and subsequently towards the equator. How the opposite polarities of kinetochore motors are regulated in space and time to drive congression of peripheral chromosomes only now starts to be understood. This appears to be regulated by position-dependent phosphorylation of both Dynein and CENP-E and by spindle microtubule diversity by means of tubulin post-translational modifications. This so-called “tubulin code” might work as a navigation system that selectively guides kinetochore motors with opposite polarities along specific spindle microtubule populations, ultimately leading to the congression of peripheral chromosomes. We propose an integrated model of chromosome congression in mammalian cells that depends essentially on the following parameters: (1) chromosome position relative to the spindle poles after nuclear envelope breakdown; (2) establishment of stable end-on kinetochore-microtubule attachments and bi-orientation; (3) coordination between kinetochore- and arm-associated motors; and (4) spatial signatures associated with post-translational modifications of specific spindle microtubule populations. The physiological consequences of abnormal chromosome congression, as well as the therapeutic potential of inhibiting chromosome congression are also discussed. Full article
(This article belongs to the Special Issue Mechanisms of Mitotic Chromosome Segregation) Printed Edition available
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Open AccessReview The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis
Biology 2017, 6(1), 12; doi:10.3390/biology6010012
Received: 10 November 2016 / Revised: 24 January 2017 / Accepted: 26 January 2017 / Published: 8 February 2017
PDF Full-text (3360 KB) | HTML Full-text | XML Full-text
Abstract
Mistakes during cell division frequently generate changes in chromosome content, producing aneuploid or polyploid progeny cells. Polyploid cells may then undergo abnormal division to generate aneuploid cells. Chromosome segregation errors may also involve fragments of whole chromosomes. A major consequence of segregation defects
[...] Read more.
Mistakes during cell division frequently generate changes in chromosome content, producing aneuploid or polyploid progeny cells. Polyploid cells may then undergo abnormal division to generate aneuploid cells. Chromosome segregation errors may also involve fragments of whole chromosomes. A major consequence of segregation defects is change in the relative dosage of products from genes located on the missegregated chromosomes. Abnormal expression of transcriptional regulators can also impact genes on the properly segregated chromosomes. The consequences of these perturbations in gene expression depend on the specific chromosomes affected and on the interplay of the aneuploid phenotype with the environment. Most often, these novel chromosome distributions are detrimental to the health and survival of the organism. However, in a changed environment, alterations in gene copy number may generate a more highly adapted phenotype. Chromosome segregation errors also have important implications in human health. They may promote drug resistance in pathogenic microorganisms. In cancer cells, they are a source for genetic and phenotypic variability that may select for populations with increased malignance and resistance to therapy. Lastly, chromosome segregation errors during gamete formation in meiosis are a primary cause of human birth defects and infertility. This review describes the consequences of mitotic and meiotic errors focusing on novel concepts and human health. Full article
(This article belongs to the Special Issue Mechanisms of Mitotic Chromosome Segregation) Printed Edition available
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Open AccessReview Metaphase Spindle Assembly
Biology 2017, 6(1), 8; doi:10.3390/biology6010008
Received: 3 October 2016 / Revised: 17 January 2017 / Accepted: 19 January 2017 / Published: 3 February 2017
Cited by 1 | PDF Full-text (2339 KB) | HTML Full-text | XML Full-text
Abstract
A microtubule-based bipolar spindle is required for error-free chromosome segregation during cell division. In this review I discuss the molecular mechanisms required for the assembly of this dynamic micrometer-scale structure in animal cells. Full article
(This article belongs to the Special Issue Mechanisms of Mitotic Chromosome Segregation) Printed Edition available
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Open AccessReview Mitotic Spindle Assembly in Land Plants: Molecules and Mechanisms
Biology 2017, 6(1), 6; doi:10.3390/biology6010006
Received: 1 October 2016 / Revised: 29 November 2016 / Accepted: 8 January 2017 / Published: 25 January 2017
Cited by 3 | PDF Full-text (1071 KB) | HTML Full-text | XML Full-text
Abstract
In textbooks, the mitotic spindles of plants are often described separately from those of animals. How do they differ at the molecular and mechanistic levels? In this chapter, we first outline the process of mitotic spindle assembly in animals and land plants. We
[...] Read more.
In textbooks, the mitotic spindles of plants are often described separately from those of animals. How do they differ at the molecular and mechanistic levels? In this chapter, we first outline the process of mitotic spindle assembly in animals and land plants. We next discuss the conservation of spindle assembly factors based on database searches. Searches of >100 animal spindle assembly factors showed that the genes involved in this process are well conserved in plants, with the exception of two major missing elements: centrosomal components and subunits/regulators of the cytoplasmic dynein complex. We then describe the spindle and phragmoplast assembly mechanisms based on the data obtained from robust gene loss-of-function analyses using RNA interference (RNAi) or mutant plants. Finally, we discuss future research prospects of plant spindles. Full article
(This article belongs to the Special Issue Mechanisms of Mitotic Chromosome Segregation) Printed Edition available
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Open AccessReview A Molecular View of Kinetochore Assembly and Function
Biology 2017, 6(1), 5; doi:10.3390/biology6010005
Received: 13 December 2016 / Revised: 16 January 2017 / Accepted: 17 January 2017 / Published: 24 January 2017
Cited by 4 | PDF Full-text (4961 KB) | HTML Full-text | XML Full-text
Abstract
Kinetochores are large protein assemblies that connect chromosomes to microtubules of the mitotic and meiotic spindles in order to distribute the replicated genome from a mother cell to its daughters. Kinetochores also control feedback mechanisms responsible for the correction of incorrect microtubule attachments,
[...] Read more.
Kinetochores are large protein assemblies that connect chromosomes to microtubules of the mitotic and meiotic spindles in order to distribute the replicated genome from a mother cell to its daughters. Kinetochores also control feedback mechanisms responsible for the correction of incorrect microtubule attachments, and for the coordination of chromosome attachment with cell cycle progression. Finally, kinetochores contribute to their own preservation, across generations, at the specific chromosomal loci devoted to host them, the centromeres. They achieve this in most species by exploiting an epigenetic, DNA-sequence-independent mechanism; notable exceptions are budding yeasts where a specific sequence is associated with centromere function. In the last 15 years, extensive progress in the elucidation of the composition of the kinetochore and the identification of various physical and functional modules within its substructure has led to a much deeper molecular understanding of kinetochore organization and the origins of its functional output. Here, we provide a broad summary of this progress, focusing primarily on kinetochores of humans and budding yeast, while highlighting work from other models, and present important unresolved questions for future studies. Full article
(This article belongs to the Special Issue Mechanisms of Mitotic Chromosome Segregation) Printed Edition available
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Open AccessReview Mechanisms to Avoid and Correct Erroneous Kinetochore-Microtubule Attachments
Biology 2017, 6(1), 1; doi:10.3390/biology6010001
Received: 3 November 2016 / Revised: 24 December 2016 / Accepted: 28 December 2016 / Published: 5 January 2017
Cited by 2 | PDF Full-text (2317 KB) | HTML Full-text | XML Full-text
Abstract
In dividing vertebrate cells multiple microtubules must connect to mitotic kinetochores in a highly stereotypical manner, with each sister kinetochore forming microtubule attachments to only one spindle pole. The exact sequence of events by which this goal is achieved varies considerably from cell
[...] Read more.
In dividing vertebrate cells multiple microtubules must connect to mitotic kinetochores in a highly stereotypical manner, with each sister kinetochore forming microtubule attachments to only one spindle pole. The exact sequence of events by which this goal is achieved varies considerably from cell to cell because of the variable locations of kinetochores and spindle poles, and randomness of initial microtubule attachments. These chance encounters with the kinetochores nonetheless ultimately lead to the desired outcome with high fidelity and in a limited time frame, providing one of the most startling examples of biological self-organization. This chapter discusses mechanisms that contribute to accurate chromosome segregation by helping dividing cells to avoid and resolve improper microtubule attachments. Full article
(This article belongs to the Special Issue Mechanisms of Mitotic Chromosome Segregation) Printed Edition available
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Open AccessReview A Brief History of Research on Mitotic Mechanisms
Biology 2016, 5(4), 55; doi:10.3390/biology5040055
Received: 1 October 2016 / Revised: 24 November 2016 / Accepted: 25 November 2016 / Published: 21 December 2016
Cited by 1 | PDF Full-text (8730 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
This chapter describes in summary form some of the most important research on chromosome segregation, from the discovery and naming of mitosis in the nineteenth century until around 1990. It gives both historical and scientific background for the nine chapters that follow, each
[...] Read more.
This chapter describes in summary form some of the most important research on chromosome segregation, from the discovery and naming of mitosis in the nineteenth century until around 1990. It gives both historical and scientific background for the nine chapters that follow, each of which provides an up-to-date review of a specific aspect of mitotic mechanism. Here, we trace the fruits of each new technology that allowed a deeper understanding of mitosis and its underlying mechanisms. We describe how light microscopy, including phase, polarization, and fluorescence optics, provided descriptive information about mitotic events and also enabled important experimentation on mitotic functions, such as the dynamics of spindle fibers and the forces generated for chromosome movement. We describe studies by electron microscopy, including quantitative work with serial section reconstructions. We review early results from spindle biochemistry and genetics, coupled to molecular biology, as these methods allowed scholars to identify key molecular components of mitotic mechanisms. We also review hypotheses about mitotic mechanisms whose testing led to a deeper understanding of this fundamental biological event. Our goal is to provide modern scientists with an appreciation of the work that has laid the foundations for their current work and interests. Full article
(This article belongs to the Special Issue Mechanisms of Mitotic Chromosome Segregation) Printed Edition available
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Open AccessReview Anaphase B
Biology 2016, 5(4), 51; doi:10.3390/biology5040051
Received: 28 September 2016 / Revised: 30 November 2016 / Accepted: 1 December 2016 / Published: 8 December 2016
Cited by 3 | PDF Full-text (3356 KB) | HTML Full-text | XML Full-text
Abstract
Anaphase B spindle elongation is characterized by the sliding apart of overlapping antiparallel interpolar (ip) microtubules (MTs) as the two opposite spindle poles separate, pulling along disjoined sister chromatids, thereby contributing to chromosome segregation and the propagation of all cellular life. The major
[...] Read more.
Anaphase B spindle elongation is characterized by the sliding apart of overlapping antiparallel interpolar (ip) microtubules (MTs) as the two opposite spindle poles separate, pulling along disjoined sister chromatids, thereby contributing to chromosome segregation and the propagation of all cellular life. The major biochemical “modules” that cooperate to mediate pole–pole separation include: (i) midzone pushing or (ii) braking by MT crosslinkers, such as kinesin-5 motors, which facilitate or restrict the outward sliding of antiparallel interpolar MTs (ipMTs); (iii) cortical pulling by disassembling astral MTs (aMTs) and/or dynein motors that pull aMTs outwards; (iv) ipMT plus end dynamics, notably net polymerization; and (v) ipMT minus end depolymerization manifest as poleward flux. The differential combination of these modules in different cell types produces diversity in the anaphase B mechanism. Combinations of antagonist modules can create a force balance that maintains the dynamic pre-anaphase B spindle at constant length. Tipping such a force balance at anaphase B onset can initiate and control the rate of spindle elongation. The activities of the basic motor filament components of the anaphase B machinery are controlled by a network of non-motor MT-associated proteins (MAPs), for example the key MT cross-linker, Ase1p/PRC1, and various cell-cycle kinases, phosphatases, and proteases. This review focuses on the molecular mechanisms of anaphase B spindle elongation in eukaryotic cells and briefly mentions bacterial DNA segregation systems that operate by spindle elongation. Full article
(This article belongs to the Special Issue Mechanisms of Mitotic Chromosome Segregation) Printed Edition available
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Open AccessReview A Cell Biological Perspective on Past, Present and Future Investigations of the Spindle Assembly Checkpoint
Biology 2016, 5(4), 44; doi:10.3390/biology5040044
Received: 4 October 2016 / Revised: 10 November 2016 / Accepted: 14 November 2016 / Published: 19 November 2016
Cited by 3 | PDF Full-text (951 KB) | HTML Full-text | XML Full-text
Abstract
The spindle assembly checkpoint (SAC) is a quality control mechanism that ensures accurate chromosome segregation during cell division. It consists of a mechanochemical signal transduction mechanism that senses the attachment of chromosomes to the spindle, and a signaling cascade that inhibits cell division
[...] Read more.
The spindle assembly checkpoint (SAC) is a quality control mechanism that ensures accurate chromosome segregation during cell division. It consists of a mechanochemical signal transduction mechanism that senses the attachment of chromosomes to the spindle, and a signaling cascade that inhibits cell division if one or more chromosomes are not attached. Extensive investigations of both these component systems of the SAC have synthesized a comprehensive understanding of the underlying molecular mechanisms. This review recounts the milestone results that elucidated the SAC, compiles a simple model of the complex molecular machinery underlying the SAC, and highlights poorly understood facets of the biochemical design and cell biological operation of the SAC that will drive research forward in the near future. Full article
(This article belongs to the Special Issue Mechanisms of Mitotic Chromosome Segregation) Printed Edition available
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title: Foundations of Modern Research on Mitotic Mechanisms
Authors: J. Richard McIntosh 1 and Thomas S. Hays 2
Affiliation: 1 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309-0347, USA; E-Mail: richard.mcintosh@colorado.edu
2 Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55108, USA; E-Mail: haysx001@umn.edu

Type of Paper: Review
Title: Kinetochore Structure
Author: Andrea Musacchio
Affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany; E-Mail: Andrea.Musacchio@mpi-dortmund.mpg.de

Type of Paper: Review
Title: Kinetochore Assembly and Function
Author: Arshad Desai
Affiliation: Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; E-Mail: abdesai@ucsd.edu

Type of Paper: Review
Title: Spindle Assembly
Author: Tarun Kapoor
Affiliation: Laboratory of Chemistry and Cell Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; E-Mail: Tarun.Kapoor@rockefeller.edu

Type of Paper: Review
Title: Spindle Assembly in Plant Cells
Author: Gohta Goshinma
Affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan; E-Mail: goshima@bio.nagoya-u.ac.jp

Type of Paper: Review
Title: Chromosome Congression to the Metaphase Plate
Author: Edward D. Salmon
Affiliation: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; E-Mail: tsalmon@email.unc.edu

Type of Paper: Review
Title: The Spindle Assembly Checkpoint
Author: Ajit P. Joglekar
Affiliation: Cell and Developmental Biology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA; E-Mail: ajitj@umich.edu

Type of Paper: Review
Title: Correcting Mitotic Errors
Author: Ekaterina L. Grishchuk
Affiliation: Physiology Department, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; E-Mail: gekate@mail.med.upenn.edu

Type of Paper: Review
Title: Anaphase A
Author: Charles L. Asbury
Affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA; E-Mail: casbury@u.washington.edu

Type of Paper: Review
Title: Anaphase B
Author: Jonathan M. Scholey
Affiliation: Department of Molecular and Cell Biology, University of California at Davis, Davis, CA 95616, USA; E-Mail: jmscholey@ucdavis.edu

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