4D imaging reveals a shift in chromosome segregation dynamics during mouse pre-implantation development

Yamagata, Kazuya; FitzHarris, Greg

doi:10.4161/cc.23052

Cited by 20 publications

(18 citation statements)

References 45 publications

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“…Complete 4D datasets of embryo development (as in Fig. 3) were obtained as previously described (23,32). Briefly, 61 optical sections were obtained at 225-s intervals for 90 h using a CSU10 Yokagawa Nipkow disk system, mounted on an Olympus IX-71 inverted microscope.…”

Section: Methodsmentioning

confidence: 99%

Micronucleus formation causes perpetual unilateral chromosome inheritance in mouse embryos

Vázquez-Diez

Yamagata

Trivedi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Chromosome segregation defects in cancer cells lead to encapsulation of chromosomes in micronuclei (MN), small nucleus-like structures within which dangerous DNA rearrangements termed chromothripsis can occur. Here we uncover a strikingly different consequence of MN formation in preimplantation development. We find that chromosomes from within MN become damaged and fail to support a functional kinetochore. MN are therefore not segregated, but are instead inherited by one of the two daughter cells. We find that the same MN can be inherited several times without rejoining the principal nucleus and without altering the kinetics of cell divisions. MN motion is passive, resulting in an even distribution of MN across the first two cell lineages. We propose that perpetual unilateral MN inheritance constitutes an unexpected mode of chromosome missegregation, which could contribute to the high frequency of aneuploid cells in mammalian embryos, but simultaneously may serve to insulate the early embryonic genome from chromothripsis.A ccurate chromosome segregation is achieved by correct attachment of spindle microtubules to kinetochores, complex proteinaceous structures that assemble on centromeric DNA. Misattachment can cause so-called lagging chromosomes during anaphase (1), which are a hallmark of chromosomally unstable cells (2), and can result in micronuclei (MN)-small nucleus-like bodies that form if a chromosome remains separate from the main group of chromosomes at the time of nuclear envelope reformation. MN have long been used as a marker of genetic fidelity. For example, MN may be predictive of tumorigenicity and can be used to screen chemicals for genotoxicity (3-5). However, the cellular impact of MN formation is poorly understood. Recent studies found that chromosomes within MN become heavily damaged, causing DNA rearrangements (6-9). Paired with reincorporation of the MN chromosome into the main nucleus (principal nucleus; PN) during the next cell cycle (7, 9, 10), this provided an elegant explanation for chromosome-specific extensive rearrangements seen in many cancer cells, termed chromothripsis (11,12). In the present study we show that the outcome of MN formation is markedly different in the preimplantation mammalian embryo.Chromosomal mosaisicm is common in mammalian preimplantation embryos, up to 50% of human embryos produced in fertility clinics containing some aneuploid cells resulting from early mitotic errors (13-16), for which there is currently no clear cellular explanation. Simultaneously, early embryos frequently exhibit MN, the causes and consequences of which are unknown (17, 18). Here we pair long-term live 4D microscopy with high-resolution fixed embryo analysis to analyze the causes and consequences of naturally occurring MN in mouse embryos. Our experiments reveal an unexpected series of events in which chromosomes from within MN do not rejoin the principal nucleus, but are repeatedly inherited by only one daughter cell. We propose that this mechanism should generate a cascade of aneuploi...

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Section: Methodsmentioning

confidence: 99%

Micronucleus formation causes perpetual unilateral chromosome inheritance in mouse embryos

Vázquez-Diez

Yamagata

Trivedi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The mitotic spindle can vary from submicron in yeast to~60 mm in Xenopus eggs, whereas the cells that house these spindles may range from a few microns up to~1 mm (5). Recent experiments reveal a striking relationship between the spindle size and cell size (5)(6)(7)(8)(9)(10)(11), as well as between various dimensions of the spindle (e.g., spindle width, spindle length, spindle pole size) (7,(11)(12)(13)(14). Most intriguingly, the spindle size scales linearly with the cell size up to a certain limit; and such a biphasic scaling relationship, as well as the critical cell size and spindle size for the biphasic transition, appear surprisingly consistent across metazoan species (5,8,10).…”

Section: Introductionmentioning

confidence: 99%

Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint

Chen

Liu

2016

Biophysical Journal

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Chromosome segregation during mitosis hinges on proper assembly of the microtubule spindle that establishes bipolar attachment to each chromosome. Experiments demonstrate allometry of mitotic spindles and a universal scaling relationship between spindle size and cell size across metazoans, which indicates a conserved principle of spindle assembly at play during evolution. However, the nature of this principle is currently unknown. Researchers have focused on deriving the mechanistic underpinning of the size scaling from the mechanical aspects of the spindle assembly process. In this work we take a different standpoint and ask: What is the size scaling for? We address this question from the functional perspectives of spindle assembly checkpoint (SAC). SAC is the critical surveillance mechanism that prevents premature chromosome segregation in the presence of unattached or misattached chromosomes. The SAC signal gets silenced after and only after the last chromosome-spindle attachment in mitosis. We previously established a model that explains the robustness of SAC silencing based on spindle-mediated spatiotemporal regulation of SAC proteins. Here, we refine the previous model, and find that robust and timely SAC silencing entails proper size scaling of mitotic spindle. This finding provides, to our knowledge, a novel, function-oriented angle toward understanding the observed spindle allometry, and the universal scaling relationship between spindle size and cell size in metazoans. In a broad sense, the functional requirement of robust SAC silencing could have helped shape the spindle assembly mechanism in evolution.

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“…The spindle in the zygote is substantially shorter than the diameter of the cell, suggesting length regulation is entirely intrinsic. But from the second mitosis onwards, as cell size decreases, spindle size approaches the diameter of the cell, indicating extrinsic regulation (Courtois et al 2012, Yamagata & FitzHarris 2013, as has been seen Figure 3 Chromosome segregation during mitosis and mechanisms preventing errors. Top: Schematic of the major physical events during mitosis.…”

Section: Spindle Idiosyncrasies In the Early Mammalian Embryomentioning

confidence: 89%

“…Contrastingly, cytoplasmic removal in later preimplantation divisions (4-8 cell and onwards), when spindle length is similar to cell length, shortens the spindle (Courtois et al 2012). Similarly, whereas 1-and 2-cell embryos exhibit a pronounced anaphase B spindle elongation, the extent and speed of spindle elongation during anaphase is decreased thereafter as the size of the cell becomes a limiting factor to spindle elongation (Yamagata & FitzHarris 2013). Hence, reductive divisions impose ever-changing limits on spindle structure and dynamics during preimplantation development.…”

Section: Spindle Idiosyncrasies In the Early Mammalian Embryomentioning

confidence: 99%

“…Hence, reductive divisions impose ever-changing limits on spindle structure and dynamics during preimplantation development. Curiously, the spindle in the first mitotic division is proportionally smaller than in the second division, despite a far greater cell size (Courtois et al 2012, Yamagata & FitzHarris 2013, suggesting spindle length during the first mitosis is subject to different, perhaps more meiotic-like, regulatory mechanisms, than later divisions. Whether this is mediated by remnants of cytostatic factor components that may persist in the first mitosis, remains to be seen (Kubiak & Ciemerych 2001, Maller et al 2002.…”

Section: Spindle Idiosyncrasies In the Early Mammalian Embryomentioning

confidence: 99%

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Causes and consequences of chromosome segregation error in preimplantation embryos

Vázquez-Diez¹,

FitzHarris²

2018

Reproduction

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Errors in chromosome segregation are common during the mitotic divisions of preimplantation development in mammalian embryos, giving rise to so-called 'mosaic' embryos possessing a mixture of euploid and aneuploid cells. Mosaicism is widely considered to be detrimental to embryo quality and is frequently used as criteria to select embryos for transfer in human fertility clinics. However, despite the clear clinical importance, the underlying defects in cell division that result in mosaic aneuploidy remain elusive. In this review, we summarise recent findings from clinical and animal model studies that provide new insights into the fundamental mechanisms of chromosome segregation in the highly unusual cellular environment of early preimplantation development and consider recent clues as to why errors should commonly occur in this setting. We furthermore discuss recent evidence suggesting that mosaicism is not an irrevocable barrier to a healthy pregnancy. Understanding the causes and biological impacts of mosaic aneuploidy will be pivotal in the development and fine-tuning of clinical embryo selection methods.Reproduction (2018) 155 R63-R76

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4D imaging reveals a shift in chromosome segregation dynamics during mouse pre-implantation development

Cited by 20 publications

References 45 publications

Micronucleus formation causes perpetual unilateral chromosome inheritance in mouse embryos

Micronucleus formation causes perpetual unilateral chromosome inheritance in mouse embryos

Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint

Causes and consequences of chromosome segregation error in preimplantation embryos

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