A prometaphase mechanism of securin destruction is essential for meiotic progression in mouse oocytes

AbstractSuccessful cell division relies on the timely removal of key cell cycle proteins such as securin. Securin inhibits separase, which cleaves the cohesin rings holding chromosomes together. Securin must be depleted before anaphase to ensure chromosome segregation occurs with anaphase. Here we find that in meiosis I, mouse oocytes contain an excess of securin over separase. We reveal a mechanism that promotes excess securin destruction in prometaphase I. Importantly, this mechanism relies on two phenylalanine residues within the separase-interacting segment (SIS) of securin that are only exposed when securin is not bound to separase. We suggest that these residues facilitate the removal of non-separase-bound securin ahead of metaphase, as inhibiting this period of destruction by mutating both residues causes the majority of oocytes to arrest in meiosis I. We further propose that cellular securin levels exceed the amount an oocyte is capable of removing in metaphase alone, such that the prometaphase destruction mechanism identified here is essential for correct meiotic progression in mouse oocytes.

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Distinct classes of lagging chromosome underpin age-related oocyte aneuploidy in mouse

10.1101/2021.01.30.428896 ◽

2021 ◽

Author(s):

Aleksandar I. Mihajlović ◽

Jenna Haverfield ◽

Greg FitzHarris

Keyword(s):

Cell Cycle ◽

Chromosome Segregation ◽

Maternal Age ◽

Class Ii ◽

Class I ◽

Mouse Oocytes ◽

Age Related ◽

Lagging Chromosome ◽

Segregation Phenomenon ◽

Meiosis I

SUMMARYChromosome segregation errors that cause oocyte aneuploidy increase in frequency with maternal age and are considered a major contributing factor of age-related fertility decline in females. A common age-associated chromosome segregation phenomenon in oocytes is the lagging anaphase chromosome, but whether anaphase laggards actually missegregate and cause aneuploidy is unclear. Here we show unexpectedly that lagging chromosomes in mouse oocytes comprise two mechanistically distinct classes of motion that we refer to as ‘Class-I’ and ‘Class-II’. We use imaging approaches and mechanistic interventions to dissociate the two classes, and find that whereas Class-II laggards are benign, Class-I laggards can directly cause aneuploidy. Most notably, a controlled prolongation of meiosis-I specifically lessens Class-I lagging to prevent aneuploidy. Our data thus reveal lagging chromosomes to be a cause of age-related aneuploidy in mouse oocytes and suggest that manipulating the cell cycle could increase the yield of useful oocytes in some contexts.

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Cyclin B3 is specifically required for metaphase to anaphase transition in mouse oocyte meiosis I

10.1101/390351 ◽

2018 ◽

Cited By ~ 1

Author(s):

Yufei Li ◽

Leyun Wang ◽

Linlin Zhang ◽

Zhengquan He ◽

Guihai Feng ◽

...

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Chromosome Segregation ◽

Mammalian Species ◽

Cell Cycle Control ◽

Special Role ◽

List Type ◽

Oocyte Meiosis ◽

Cyclin B3 ◽

Meiosis I

AbstractMeiosis, a cell division to generate gametes for sexual reproduction in eukaryotes, executes a single round of DNA replication and two successive rounds of chromosome segregation [1]. The extraordinary reliability of the meiotic cycle requires the activities of cyclin-dependent kinases (Cdks) associated with specific cyclins [2-4]. Cyclins are the regulatory subunits of protein kinases, which are the main regulators of maturation promoting factor or mitosis promoting factor (MPF) [5, 6] and anaphase-promoting complex/cyclosome (APC/C) [7, 8] in eukaryotic cell division. But how cyclins collaborate to control meiosis is still largely unknown. Cyclin B3 (Ccnb3) shares homology with A- and B-type cyclins [9], and is conserved during higher eukaryote evolution [10-17]. Previous studies have shown that Ccnb3-deleted females are sterile with oocytes unable to complete meiosis I in Drosophila [18], implying that Ccnb3 may have a special role in meiosis. To clarify the function of Ccnb3 in meiosis in mammalian species, we generated Ccnb3 mutant mice by CRISPR/Cas9, and found that Ccnb3 mutation caused female infertility with the failure of metaphase-anaphase transition in meiosis I. Ccnb3 was necessary for APC/C activation to initiate anaphase I, but not required for oocytes maturation, meiosis II progression, or early embryonic development. Our study reveals the differential cell cycle regulation between meiosis I and meiosis II, as well as meiosis between males and females, which shed light on the cell cycle control of meiosis.HighlightsIdentification of a female meiosis-specific cyclin in mouseCyclin B3 is required for metaphase-anaphase transition in oocyte meiosis ICyclin B3 is not essential for oocyte maturation and sister chromosome segregationCyclin B3 is necessary for APC/C activation and MPF kinase activity through Cdk1

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Increased Expression of Maturation Promoting Factor Components Speeds Up Meiosis in Oocytes from Aged Females

International Journal of Molecular Sciences ◽

10.3390/ijms19092841 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2841 ◽

Cited By ~ 5

Author(s):

Marketa Koncicka ◽

Anna Tetkova ◽

Denisa Jansova ◽

Edgar Del Llano ◽

Lenka Gahurova ◽

...

Keyword(s):

Chromosome Segregation ◽

Maternal Age ◽

Germ Line ◽

Nuclear Lamina ◽

Nuclear Envelope Breakdown ◽

Meiotic Progression ◽

Translational Activity ◽

Female Germ Line ◽

Mammalian Female ◽

Meiosis I

The rate of chromosome segregation errors that emerge during meiosis I in the mammalian female germ line are known to increase with maternal age; however, little is known about the underlying molecular mechanism. The objective of this study was to analyze meiotic progression of mouse oocytes in relation to maternal age. Using the mouse as a model system, we analyzed the timing of nuclear envelope breakdown and the morphology of the nuclear lamina of oocytes obtained from young (2 months old) and aged females (12 months old). Oocytes obtained from older females display a significantly faster progression through meiosis I compared to the ones obtained from younger females. Furthermore, in oocytes from aged females, lamin A/C structures exhibit rapid phosphorylation and dissociation. Additionally, we also found an increased abundance of MPF components and increased translation of factors controlling translational activity in the oocytes of aged females. In conclusion, the elevated MPF activity observed in aged female oocytes affects precocious meiotic processes that can multifactorially contribute to chromosomal errors in meiosis I.

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The spindle checkpoint protein Mad2 regulates APC/C activity during prometaphase and metaphase of meiosis I in Saccharomyces cerevisiae

Molecular Biology of the Cell ◽

10.1091/mbc.e11-04-0378 ◽

2011 ◽

Vol 22 (16) ◽

pp. 2848-2861 ◽

Cited By ~ 21

Author(s):

Dai Tsuchiya ◽

Claire Gonzalez ◽

Soni Lacefield

Keyword(s):

Saccharomyces Cerevisiae ◽

Cell Cycle ◽

Chromosome Segregation ◽

Meiotic Division ◽

Spindle Checkpoint ◽

Yeast Cells ◽

Meiotic Cell ◽

Checkpoint Protein ◽

Sister Chromatids ◽

Meiosis I

In many eukaryotes, disruption of the spindle checkpoint protein Mad2 results in an increase in meiosis I nondisjunction, suggesting that Mad2 has a conserved role in ensuring faithful chromosome segregation in meiosis. To characterize the meiotic function of Mad2, we analyzed individual budding yeast cells undergoing meiosis. We find that Mad2 sets the duration of meiosis I by regulating the activity of APCCdc20. In the absence of Mad2, most cells undergo both meiotic divisions, but securin, a substrate of the APC/C, is degraded prematurely, and prometaphase I/metaphase I is accelerated. Some mad2Δ cells have a misregulation of meiotic cell cycle events and undergo a single aberrant division in which sister chromatids separate. In these cells, both APCCdc20 and APCAma1 are prematurely active, and meiosis I and meiosis II events occur in a single meiotic division. We show that Mad2 indirectly regulates APCAma1 activity by decreasing APCCdc20 activity. We propose that Mad2 is an important meiotic cell cycle regulator that ensures the timely degradation of APC/C substrates and the proper orchestration of the meiotic divisions.

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Aurora-C Kinase Deficiency Causes Cytokinesis Failure in Meiosis I and Production of Large Polyploid Oocytes in Mice

Molecular Biology of the Cell ◽

10.1091/mbc.e10-02-0170 ◽

2010 ◽

Vol 21 (14) ◽

pp. 2371-2383 ◽

Cited By ~ 88

Author(s):

Kuo-Tai Yang ◽

Shu-Kuei Li ◽

Chih-Chieh Chang ◽

Chieh-Ju C. Tang ◽

Yi-Nan Lin ◽

...

Keyword(s):

Chromosome Segregation ◽

Female Mouse ◽

Histone H3 ◽

Aurora B ◽

Binding Motif ◽

Mouse Oocytes ◽

Microtubule Attachment ◽

H3 Phosphorylation ◽

Histone H3 Phosphorylation ◽

Meiosis I

We previously isolated Aurora-C/Aie1 in a screen for kinases expressed in mouse sperm and eggs. Here, we show the localization of endogenous Aurora-C and examine its roles during female mouse meiosis. Aurora-C was detected at the centromeres and along the chromosome arms in prometaphase I–metaphase I and was concentrated at centromeres at metaphase II, in which Aurora-C also was phosphorylated at Thr171. During the anaphase I–telophase I transition, Aurora-C was dephosphorylated and relocalized to the midzone and midbody. Microinjection of the kinase-deficient Aurora-C (AurC-KD) mRNA into mouse oocytes significantly inhibited Aurora-C activity and caused multiple defects, including chromosome misalignment, abnormal kinetochore–microtubule attachment, premature chromosome segregation, and cytokinesis failure in meiosis I. Furthermore, AurC-KD reduced Aurora-C and histone H3 phosphorylation and inhibited kinetochore localization of Bub1 and BubR1. Similar effects also were observed in the oocytes injected with INCNEP-delIN mRNAs, in which the Aurora-C binding motif was removed. The most dramatic effect observed in AurC-KD–injected oocytes is cytokinesis failure in meiosis I, resulting in producing large polyploid oocytes, a pattern similar to Aurora-C deficiency human spermatozoa. Surprisingly, we detected no Aurora-B protein in mouse oocytes. We propose that Aurora-C, but not Aurora-B, plays essential roles in female mouse meiosis.

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Bacterial chromosome segregation.

Acta Biochimica Polonica ◽

10.18388/abp.2005_3481 ◽

2005 ◽

Vol 52 (1) ◽

pp. 1-34 ◽

Cited By ~ 31

Author(s):

Aneta A Bartosik ◽

Grazyna Jagura-Burdzy

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Chromosome Segregation ◽

Copy Number ◽

Bacterial Cells ◽

Replication Machinery ◽

Rapid Separation ◽

Dna Segregation ◽

Low Copy Number ◽

Bacterial Chromosomes

In most bacteria two vital processes of the cell cycle: DNA replication and chromosome segregation overlap temporally. The action of replication machinery in a fixed location in the cell leads to the duplication of oriC regions, their rapid separation to the opposite halves of the cell and the duplicated chromosomes gradually moving to the same locations prior to cell division. Numerous proteins are implicated in co-replicational DNA segregation and they will be characterized in this review. The proteins SeqA, SMC/MukB, MinCDE, MreB/Mbl, RacA, FtsK/SpoIIIE playing different roles in bacterial cells are also involved in chromosome segregation. The chromosomally encoded ParAB homologs of active partitioning proteins of low-copy number plasmids are also players, not always indispensable, in the segregation of bacterial chromosomes.

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Selective dephosphorylation by PP2A-B55 directs the meiosis I - meiosis II transition in oocytes

10.1101/2020.08.21.260216 ◽

2020 ◽

Author(s):

S. Zachary Swartz ◽

Hieu T. Nguyen ◽

Brennan C. McEwan ◽

Mark E. Adamo ◽

Iain M. Cheeseman ◽

...

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Time Course ◽

Phosphorylation Site ◽

Sea Star ◽

Meiotic Stage ◽

Protein Levels ◽

Substrate Preferences ◽

Embryonic Cleavage ◽

Meiosis I

AbstractMeiosis is a specialized cell cycle that requires sequential changes to the cell division machinery to facilitate changing functions. To define the mechanisms that enable the oocyte-to-embryo transition, we performed time-course proteomics in sea star oocytes from prophase I through the first embryonic cleavage. Although protein levels are broadly stable, dynamic waves of phosphorylation underlie each meiotic stage. We find that the phosphatase PP2A-B55 is reactivated at the Meiosis I/II transition resulting in the preferential dephosphorylation of threonine residues. Selective dephosphorylation is critical for directing the MI / MII transition as altering PP2A-B55 substrate preferences disrupts key cell cycle events after meiosis I. In addition, threonine to serine substitution of a conserved phosphorylation site in the substrate INCENP prevents its relocalization at anaphase I. Thus, through its inherent phospho-threonine preference, PP2A-B55 rewires the cell division apparatus to direct the MI / MII transition.

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Cdc14 phosphatase directs centrosome re-duplication at the meiosis I to meiosis II transition in budding yeast

Wellcome Open Research ◽

10.12688/wellcomeopenres.10507.1 ◽

2017 ◽

Vol 2 ◽

pp. 2 ◽

Cited By ~ 10

Author(s):

Colette Fox ◽

Juan Zou ◽

Juri Rappsilber ◽

Adele L. Marston

Keyword(s):

Cell Cycle ◽

Dna Replication ◽

Chromosome Segregation ◽

Budding Yeast ◽

Spindle Pole Body ◽

Initial Step ◽

Mitotic Cell ◽

Spindle Pole ◽

Fluorescence And Electron Microscopy ◽

Meiosis I

Background Gametes are generated through a specialized cell division called meiosis, in which ploidy is reduced by half because two consecutive rounds of chromosome segregation, meiosis I and meiosis II, occur without intervening DNA replication. This contrasts with the mitotic cell cycle where DNA replication and chromosome segregation alternate to maintain the same ploidy. At the end of mitosis, CDKs are inactivated. This low CDK state in late mitosis/G1 allows for critical preparatory events for DNA replication and centrosome/spindle pole body (SPB) duplication. However, their execution is inhibited until S phase, where further preparatory events are also prevented. This “licensing” ensures that both the chromosomes and the centrosomes/SPBs replicate exactly once per cell cycle, thereby maintaining constant ploidy. Crucially, between meiosis I and meiosis II, centrosomes/SPBs must be re-licensed, but DNA re-replication must be avoided. In budding yeast, the Cdc14 protein phosphatase triggers CDK down regulation to promote exit from mitosis. Cdc14 also regulates the meiosis I to meiosis II transition, though its mode of action has remained unclear. Methods Fluorescence and electron microscopy was combined with proteomics to probe SPB duplication in cells with inactive or hyperactive Cdc14. Results We demonstrate that Cdc14 ensures two successive nuclear divisions by re-licensing SPBs at the meiosis I to meiosis II transition. We show that Cdc14 is asymmetrically enriched on a single SPB during anaphase I and provide evidence that this enrichment promotes SPB re-duplication. Cells with impaired Cdc14 activity fail to promote extension of the SPB half-bridge, the initial step in morphogenesis of a new SPB. Conversely, cells with hyper-active Cdc14 duplicate SPBs, but fail to induce their separation. Conclusion Our findings implicate reversal of key CDK-dependent phosphorylations in the differential licensing of cyclical events at the meiosis I to meiosis I transition.

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Wapl releases Scc1-cohesin and regulates chromosome structure and segregation in mouse oocytes

The Journal of Cell Biology ◽

10.1083/jcb.201906100 ◽

2020 ◽

Vol 219 (4) ◽

Cited By ~ 1

Author(s):

Mariana C.C. Silva ◽

Sean Powell ◽

Sabrina Ladstätter ◽

Johanna Gassler ◽

Roman Stocsits ◽

...

Keyword(s):

Residence Time ◽

Chromosome Segregation ◽

Chromosome Structure ◽

Somatic Cells ◽

Cell Types ◽

Chromosome Organization ◽

Loop Size ◽

Mouse Oocytes ◽

Single Nucleus ◽

Meiosis I

Cohesin is essential for genome folding and inheritance. In somatic cells, these functions are both mediated by Scc1-cohesin, which in mitosis is released from chromosomes by Wapl and separase. In mammalian oocytes, cohesion is mediated by Rec8-cohesin. Scc1 is expressed but neither required nor sufficient for cohesion, and its function remains unknown. Likewise, it is unknown whether Wapl regulates one or both cohesin complexes and chromosome segregation in mature oocytes. Here, we show that Wapl is required for accurate meiosis I chromosome segregation, predominantly releases Scc1-cohesin from chromosomes, and promotes production of euploid eggs. Using single-nucleus Hi-C, we found that Scc1 is essential for chromosome organization in oocytes. Increasing Scc1 residence time on chromosomes by Wapl depletion leads to vermicelli formation and intra-loop structures but, unlike in somatic cells, does not increase loop size. We conclude that distinct cohesin complexes generate loops and cohesion in oocytes and propose that the same principle applies to all cell types and species.

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Cell Division

Examining the Causal Relationship Between Genes, Epigenetics, and Human Health - Advances in Bioinformatics and Biomedical Engineering ◽

10.4018/978-1-5225-8066-9.ch004 ◽

2019 ◽

pp. 93-114

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Chromosome Number ◽

Sexual Reproduction ◽

Germ Cells ◽

Growth And Development ◽

Reduction Division ◽

Regulatory Proteins ◽

Chromosomal Number ◽

Meiosis I

Cells divide for three main reasons: growth and development, replace worn-out or injured cells, and reproduction of offspring. Cell division is part of the cell cycle divided into five distinct phases. The diploid state of the cell is the normal chromosomal number in species. During sexual reproduction, the cell's chromosome number is reduced to a haploid state to ensure constancy in chromosome number and thus continuation of the species. The process of cell division is controlled by regulatory proteins. Mitosis occurs in all body cells and is divided into four phases. Meiosis, which occurs in only the germ cells involved in reproduction, divides the chromosomes in two rounds termed meiosis I and meiosis II (reduction division). The human lifecycle starts with gametogenesis, the process that forms gametes which then combine to form a zygote. The zygote quickly becomes an embryo and develops rapidly into a foetus. This chapter explores cell division.

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