How long is meiosis

The tetrad is composed of four chromatids which make up the two homologous chromosomes. During pachynema and the next substage, diplonema, certain regions of synapsed chromosomes often become closely associated and swap corresponding segments of the DNA in a process known as chiasma. At this point, while still associated at the chiasmata, the sister chromatids start to part from each other although they are still firmly bound at the centromere; this creates the X-shape commonly associated with condensed chromosomes.

The nuclear membrane starts to dissolve by the end of diplonema and the chromosomes complete their condensation in preparation for the last substage of prophase I, diakinesis. During this part, the chiasmata terminalize move toward the ends of their respective chromatids and drift further apart, with each chromatid now bearing some newly-acquired genetic material as the result of crossing over.

Simultaneously, the centrioles, pairs of cylindrical microtubular organelles, move to opposite poles and the region containing them becomes the source for spindle fibers. These spindle fibers anchor onto the kinetochore, a macromolecule that regulates the interaction between them and the chromosome during the next stages of meiosis.

The kinetochores are attached to the centromere of each chromosome and help move the chromosomes to position along a three-dimensional plane at the middle of the cell, called the metaphase plate. The cell now prepares for metaphase I, the next step after prophase I. During metaphase I, the tetrads finish aligning along the metaphase plate, although the orientation of the chromosomes making them up is random.

The chromosomes have fully condensed by the point and are firmly associated with the spindle fibers in preparation for the next step, anaphase I. During this third stage of meiosis I, the tetrads are pulled apart by the spindle fibers, each half becoming a dyad in effect, a chromosome or two sister chromatids attached at the centromere.

Assuming that nondisjunction failure of chromosomes to separate does not occur, half of the chromosomes in the cell will be maneuvered to one pole while the rest will be pulled to the opposite pole. This migration of the chromosomes is followed by the final and brief step of meiosis I, telophase I, which, coupled with cytokinesis physical separation of the entire mother cell , produces two daughter cells. Each of these daughter cells contains 23 dyads, which sum up to 46 monads or single-stranded chromosomes.

Meiosis II follows with no further replication of the genetic material. The chromosomes briefly unravel at the end of meiosis I, and at the beginning of meiosis II they must reform into chromosomes in their newly-created cells. This brief prophase II stage [isEmbeddedIn] is followed by metaphase II, during which the chromosomes migrate toward the metaphase plate. During anaphase II, the spindle fibers again pull the chromosomes apart to opposite poles of the cell; however, this time it is the sister chromatids that are being split apart, instead of the pairs of homologous chromosomes as in the first meiotic step.

A second round of telophase this time called telophase II and cytokinesis splits each daughter cell further into two new cells. Each of these cells has 23 single-stranded chromosomes, making each cell haploid possessing 1N chromosomes.

Genetic studies have shown that Spo11 activity is essential for meiosis in yeast, because spo11 mutants fail to sporulate. As the invading strand is extended, a remarkable structure called synaptonemal complex SC develops around the paired homologues and holds them in close register, or synapsis. The stability of the SC increases as the invading strand first extends into the homologue and then is recaptured by the broken chromatid, forming double Holliday junctions.

Investigators have been able to observe the process of SC formation with electron microscopy in meiocytes from the Allium plant Figure 6. Bridges approximately nanometers long begin to form between the paired homologues following the DSB. Only a fraction of these bridges will mature into SC; moreover, not all Holliday junctions will mature into crossover sites. Gerton, J. Homologous chromosome interactions in meiosis: Diversity amidst conservation.

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Meiosis, Genetic Recombination, and Sexual Reproduction. Mitosis and Cell Division. Genetic Mechanisms of Sex Determination. Sex Chromosomes and Sex Determination. Sex Chromosomes in Mammals: X Inactivation. The argument being that with proximal exchange the bivalent has a more rigid geometry which predisposes it to bi-orientation. However in distal crossovers the bivalent could be considered more lithe and open to mono-orientation of sister kinetochores.

It has been suggested that an early prometaphase SAC-like mechanism, dependent on Mad2 and BubR1 but independent of kinetochores, is present in cells which can delay passage through mitosis Meraldi et al. Such a delay could be due to an ability to bind and so sequester cdc20 Burton and Solomon, This early mechanism is then followed by a true SAC, dependent on kinetochores, later in prometaphase Musacchio and Salmon, However the simplest experiment, addition of spindle poisons, to oocytes have all demonstrated directly the existence of a SAC by blocking oocytes in MI Wassmann et al.

Clearly, whatever the detail is in the SAC-imposed arrest upon addition of spindle poisons, such a pathway is not executed when univalent homologs are present in MI. One intriguing feature of MI is its extraordinary length. The extended period of meiosis is reflected in the dynamics of CDK1 activity, which rises abruptly in mitosis but gradually in meiosis, reaching a peak several hours after GVB Choi et al. Also important is degradation of securin to free separase. In mouse, loss of both cyclin B1 and securin occur synchronously in a period which terminates with PB1 extrusion and is dependent on APC cdc20 Reis et al.

This means cdc20 has to be resynthesized in order for oocytes to complete MI and suggests an unusual progression through chromosome segregation not observed with sisters in mitosis. Loss of cdh1 brings forward the period of APC cdc20 activity and consequently the period of cyclin B1 and securin degradation Reis et al. This premature metaphase I induces high rates of non-disjunction and leads to a disruption of the integrity of the MetII spindle probably as a consequence of a chromosome crowded spindle if hyperploid.

Similar reasoning may be behind the disruptions of the spindle structure that have been observed in human oocytes from older women Rosenbusch and Schneider, ; Shen et al. Interestingly, the SAC had not been switched off in these cdh1-depleted oocytes Reis et al.

Again, this suggests the inability of the SAC to monitor homolog bi-orientation. Free separase, generated by proteolysis of securin, can also bind CDK1 and in so doing inhibit its kinase activity Stemmann et al. The ability of CDK1 activity in oocytes to be regulated by both loss of cyclin B1 and separase binding warrants further investigation given this process is required for completion of MI. Future studies are therefore required to assess their inter-dependence.

It remains possible that SAC function could deteriorate with maternal age to account for the age-related incidence of aneuploidy. Therefore one could argue that the SAC is fully functional in oocytes from younger women, but its ability to respond to mis-alignment of homologs on the MI spindle weakens in oocytes from older females. Mad2 protein and mRNA both seem relatively unstable in MetII oocytes making such a hypothesis attractive if their instability extends to immature oocytes Ma et al.

Interestingly, these authors hypothesize that the post-ovulatory loss of Mad2 may be responsible for the increased sister chromatid segregation defects associated with post-ovulatory aging.

However, the SAC, although it can be activated by various spindle poisons, is currently thought not to be involved in maintaining the physiological arrest during MetII in mammalian oocytes, so establishing any causal link would be important Tsurumi et al. Only one study has addressed if SAC components decrease in human oocytes with age.

Here it was found that transcript levels of both Mad2 and Bub1 decrease with increasing maternal age Steuerwald et al. It will be important to corroborate this study and also provide direct evidence that the SAC is indeed compromised in oocytes from older women during MI. This would address whether the reduced transcript levels affect protein levels and consequently SAC function. Interestingly, levels of hundreds of transcripts, including cell cycle genes, have been been reported to decrease with increased maternal age in mice and women Hamatani et al.

This raises the possibility that aneuploidy may result due to falling levels of various components of the cell cycle, not just SAC members. One possible target rather than the SAC to explain age-related aneuploidy is the cohesin complex itself. Theoretically, if functionality of the complex were to decline with age it would bring together many of the loose threads presented thus far.

For example, the reduced recombination frequency, assessed by chiasmata, with age in mouse Henderson and Edwards, This was interpreted in terms of a production line because of recombination frequency being established in fetal life. However, one would observe a similar loss in chiasmata if the cohesin ties holding homologs together were loosened during dictyate arrest to the extent of separating homologs.

The fact that the cohesin complex holding homologs together is established during fetal S-phase and yet has to remain functional decades later would make it susceptible to age-related damage because it may be difficult or impossible to repair. Interestingly, these mice display an age-related incidence in aneuploidy with 4-week old mice containing oocytes with bivalents only, whereas essentially no intact homologs could be observed by 4 months Hodges et al.

The ability of the aneuploidy rate to rise with maternal age suggests that during early oocyte growth and follicle maturation cohesins may deteriorate and need to be replaced. An age-related decline in the cohesive ties holding chromosomes together coupled to an intrinsic inability of oocytes to detect or repair the resulting error is likely to constitute the etiology of some aneuploidy.

This process may be exacerbated by environmental exposure to agents which interfere with detection or repair and here it critical to best match environmental exposure to controlled laboratory conditions. Evidence exists that either neonatal or adult exposure to the weak estrogen bisphenol A BPA can induce aneuploidy in oocytes, suggesting environmental pollutants could underlie some age-related aneuploidy.

Non-disjunction in mouse is an uncommon event in most strains, yet very high rates of aneuploidy can result when mice are exposed to BPA, a common constituent of polycarbonate plastics and resins used to line food cans and make dental sealants. Aneuploidy happens when oocytes are exposed during their maturation in vitro or when oocytes are exposed to excess BPA in the animals diet Hunt et al.

Also exposure of fetal oocytes to BPA can affect the placement and number of recombination events on chromosomes, this probably generates susceptible patterns of exchange, and so leads to increased non-disjunction in treated animals Susiarjo et al. However, this is unexpected as it suggests a very early stimulatory effect of a fetal estrogen directly on oocyte recombination.

Exposure of maturing mouse oocytes to high levels of the gonadotropin FSH can also induce aneuploidy in vitro Roberts et al. Such an observation is interesting from the perspective of circulating gonadotropins being higher in older women with diminishing ovarian reserve, and the observations that increased FSH has been measured in women having DS children van Montfrans et al. This latter effect appears to be due to a decreased ovarian reserve.

The influence of FSH on aneuploidy therefore requires much further investigation. The preovulatory LH surge induces oocyte maturation and subsequent re-arrest at metaphase of the second meiotic division just prior to ovulation. Arrest at MetII and subsequent fertilization at this stage of meiosis is universal in mammals, even in Canidae oocytes which are exceptional in being ovulated at the GV stage Reynaud et al.

Re-arrest is protracted and oocytes of most animals seem to show a very good block to further progression through MetII Jones, The degradation of this oocyte-specific protein at fertilization is triggered by its phosphorylation through the concerted activity of polo kinase and calmodulin-dependent kinase II CamKII Madgwick et al.

Although polo is already active in unfertilized oocytes, CamKII is not. Recently, in frog it was demonstrated that the mos pathway is responsible for stabilizing Emi2 through p90 ribosomal S6 kinase p90rsk Inoue et al.

Interestingly, p90rsk plays no part in arresting mouse oocytes at MetII, so it will be important to establish the link between the mos and Emi2 in mammals Dumont et al. Degradation of Emi2 is responsible for the 6—7-fold increase in APC activity observed at fertilization Nixon et al.

Therefore a drop in CDK1 activity is an early event of fertilization. Also likely degraded is securin which is probably re-synthesized during MetII arrest, thus contributing to separase inhibition.

However, it is also possible that the high CDK1 activity associated with MetII arrest inhibits separase, as has been observed in other cells Gorr et al. Interestingly, the binding of CDK1 to separase leads to a mutual inhibition of activities, with binding being thought to play an essential role in inhibiting CDK1 during MI Gorr et al. Overexpression of non-degradable cyclin B1 in fertilizing oocytes blocks not only the decline in CDK1 activity, but also sister chromatid separation, suggesting that CDK1 can function as a separase inhibitor during MetII arrest Madgwick et al.

The ability of ovulated oocytes to maintain a fully functional spindle with bi-orientated sisters is probably finite and would account for the drop in oocyte quality associated with post-ovulatory aging. Interestingly, increasing female age exacerbates the decline in oocyte quality with post-ovulatory aging and is probably accounted for by a decline in their ability to maintain high CDK1 activity Tatone et al.

Metabolic, biochemical and structural parameters also decline in oocytes undergoing post-ovulatory ageing Takahashi et al.

Finally, there appears important long-term detriment to the animal derived from a post-ovulatory aged oocyte, since both its reproductive fitness as an adult and its longevity are adversely affected Tarin et al. Much of the present review has focussed on the mouse oocyte. Yet, many will argue that the human oocyte is uniquely prone to segregation errors in meiosis and therefore any other model system, including mouse, is inappropriate for the study of aneuploidy and in particular age-related aneuploidy.

Such judgement may be erroneous. Even the evolutionary distant but important model organism Drosophila melanogaster can display increased incidence of age-related aneuploidy on a background where sister chromatid cohesion is perturbed Jeffreys et al.

It is true that many strains of mice have low rates of aneuploidy and the above age-related aneuploidy in Drosophila requires disruption in the expression of the ORD gene product involved in sister chromatid cohesion. However, high, human-like levels of aneuploidy can exist without perturbation in some mice. This increase in aneuploidy was associated with a decrease in recombination frequency between homologs and is likely due to sequence divergence in the homologs of these two strains given the same phenomenon can be observed in close strains of yeasts Hunter et al.

Also some strains of mice such as CBA display higher rates of aneuploidy than other strains Eichenlaub-Ritter et al. As an aside it is important to note that achiasmate homologs are a feature of meiosis in a number of organisms, especially in Drosophila Wolf, ; Thomas et al. One mechanism to account for proper segregation of achiasmate homologs in Drosophila is heterochromatin pairing Karpen et al.

It would be interesting to determine if pairing of homologs in mammalian oocytes, independent of chiasmata, play any part in MI as it can in other organisms Gerton and Hawley, This review has had two main purposes: first, to give a broad review of the cell biology responsible for the meiotic cell cycle transitions which define the remarkable life of an oocyte; second, to put our knowledge of cell biology into a clinical context by using it to discuss our current understanding of the unique susceptibility of the oocyte to aneuploidy.

It is hoped that despite the fact that the etiology of aneuploidy is unlikely to be found in one particular meiotic defect or even pathway, our understanding of its causes will likely come from basic cell biology done on model organisms which are more tractable than human, and such knowledge will eventually feed into a clinical setting by collaborations of basic and applied researchers who together may find newer and better methods for prevention, screening and possible treatment.

Major themes basic cell biologist are likely to make substantial progress in the next decade are i how germ cells commit to entry into meiosis; ii how homologs are held together for the maintenance of cohesion and how they may deteriorate with age; iii how the oocyte remains viable during a protracted period of GV arrest; iv how the oocyte controls the segregation of homologs during the first meiotic division and v how the oocyte maintains MetII arrested and how this is detrimentally affected by post-ovulatory ageing.

Pursuit of answers to these questions will likely lead to a better understanding of aneuploidy in oocytes. The author would like to acknowledge continued funding from the Wellcome Trust. Google Scholar. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu.

Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Passage from mitosis to GV stage arrest. Passage through meiosis I. Completion of meiosis II at fertilization. Aneuploidy in oocytes: is it a human condition?

Concluding remarks. Meiosis in oocytes: predisposition to aneuploidy and its increased incidence with age. Jones Keith T. Jones 1. Oxford Academic. Revision received:. Cite Cite Keith T. Select Format Select format. Permissions Icon Permissions.

Abstract Mammalian oocytes begin meiosis in the fetal ovary, but only complete it when fertilized in the adult reproductive tract. Figure Open in new tab Download slide.

The life of a mammalian oocyte The figures depicts the life of an oocyte beginning with its inception from oogonia following PGC colonization of the ovary left to pronucleus formation following fertilization right , which marks the completion of meiosis and entry into the first embryonic cell cycle.

Aneuploidy in oocytes during meiosis I A homolog pair, aligned and under tension on a metaphase I spindle: A , C , D and E these pairs have a single crossover event, i.

Loss of cohesin with age resolves chiasmata A single crossover event has happened in fetal life for this homolog pair A. The chromosomes begin moving toward the equator of the cell.

During metaphase II, the centromeres of the paired chromatids align along the equatorial plate in both cells. Then in anaphase II, the chromosomes separate at the centromeres. The spindle fibers pull the separated chromosomes toward each pole of the cell. Finally, during telophase II, the chromosomes are enclosed in nuclear membranes. Cytokinesis follows, dividing the cytoplasm of the two cells. At the conclusion of meiosis, there are four haploid daughter cells that go on to develop into either sperm or egg cells.

Further Exploration Concept Links for further exploration cell division replication metaphase anaphase telophase linkage chromosome cytokinesis haploid prometaphase principle of segregation principle of independent assortment spindle fibers gamete DNA chromatin nucleus cytoplasm eukaryote prophase recombination principle of segregation Principles of Inheritance.

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