Meiosis:An Overview of Key Differences from Mitosis
Hiroyuki Ohkura
The Wellcome Trust Centre for Cell Biology,School of Biological Sciences,The University of Edinburgh, Edinburgh EH93JR,United Kingdom
山西永济普救寺Correspondence:h.ohkura@ed.ac.uk
Meiosis is the specialized cell division that generates gametes.In contrast to mitosis,molec-
ular mechanisms and regulation of meiosis are much less understood.Meiosis shares mech-anisms and regulation with mitosis in many aspects,but also has critical differences from mitosis.This review highlights the differences between meiosis and mitosis.Recent studies
using various model systems revealed differences in a surprisingly wide range of aspects, including cell-cycle regulation,recombination,postrecombination events,spindle asmbly, chromosome–spindle interaction,and chromosome gregation.Although a great degree of diversity can be found among organisms,meiosis-specific process,and regulation are generally conrved.
M eiosis is a special mode of cell division, which makes haploid cells from a diploid cell.It is esntial for xual reproduction in eukaryotes and diploid organisms and produces gametes,such as eggs and sperm.Sexual repro-duction is thought to be esntial for long-term survival of species,as it generates diversity and mixes the genetic materials within the species. This consists of two opposite process:meio-sis,which reduces chromosome numbers from diploid to haploid,and conjugation(fertiliza-tion),which restores the diploid state by fusion of two haploid cells.Meiosis generates diver-sity through two events:recombination and chromosome gregation.Misgregation dur-ing meiosis results in aneuploidy in progeny or fertilized eggs.In the ca of humans,it is report-ed that20%of all eggs are aneuploids,most of which areresults ofchromosome misgregation in oocytes(Hassold and Hunt2001).This is a major cau of infertility,miscarriages,and birth defects,such as Down’s syndrome,in hu-mans.Despite the medical importance,little is known about the molecular mechanisms of mei-otic chromosome gregation in humans.Un-derstanding meiosis is not only important for its own ends,but also provides unique insights into the fundamental regulation of mitosis.As many excellent reviews already cover specific as-pects of meiosis,this review gives an overview by highlighting key meiotic events and molecu-lar regulation distinct from mitosis.
CELL-CYCLE CONTROL
In eukaryotic mitotic cycles,chromosome rep-lication and gregation alternate.This is esn-tial for maintaining the genome stability.This
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is achieved by two-step regulation of replica-tion by Cdk(Tanaka and Araki2010).Thefirst step,called licensing,allows Mcm2–7to be re-cruited to form the prereplicative complex at replication origins only in G1when Cdk activity is low.An increa in Cdk kina activity,to-gether with Cdc7kina activity in late G1,trig-gers initiation of DNA replication.As a high Cdk activity inhibits the formation of the pre-replicative complex,the origin will not be li-cend until the mitotic exit.This dual function of Cdk ensures only onefiring from each repli-cation fork in one mitotic cycle.
In contrast,meiosis consists of two divisions without an intervening S pha,which is esn-tial for reducing the ploidy.Suppression of the intervening S pha is achieved by maintaining the Cdk activity sufficiently high between two meiotic divisions.In Xenopus oocytes,incom-plete degradation of cyclin B and a low amount of the W ee1kina keeps the Cdk activity high. Artificial inactivation of Cdk1after meiosis I results in DNA replication between the two di-visions(Furuno et al.1994;Iwabuchi et al.2000; Nakajo et al.2000).High Cdk1activity inhibits the formation of the prereplicative complex by preventing binding of Mcm2–7to replication origins.In Saccharomyces cerevisiae,a meiosis-specific protein kina,Ime2,also contributes to phosphorylation of some of Cdk1substrates to suppress replication between the two meiotic divisions(Holt et al.2007).
PAIRING AND RECOMBINATION
Meiotic recombination exchanges the genetic materials between two homologous chromo-somes.It is esntial not only for exchanging genetic materials to generate diversity in off-spring,but also for holding homologous chro-mosomes together through chiasma,to gre-gate chromosomes properly.
Homologous chromosomes pair along the whole length and this homologous paring is fur-ther stabilized by the formation of an elaborate structure,the synaptonemal complex.In yeast and mou,
meiotic recombination is required for proper synaptonemal complex formation (Loidl et al.1994;Baudat et al.2000;Roma-nienko and Camerini-Otero2000),whereas in Drosophila and Caenorhabditis elegans,the syn-aptonemal complex can form independently of meiotic recombination(Dernburg et al.1998; McKim et al.1998).
Recombination mechanisms themlves are largely shared in both meiotic recombination and the homologous recombination repair process in the mitotic cell cycle,but there are crucial differences.In the ca of meiosis,DNA double-strand breaks(DSBs)are obligatory rather than the result of accidental damage,as in the mitotic cell cycle.DSBs,which initiate meiotic recombination,are created by the con-rved Spo11endonuclea(Keeney et al.1997). The sites of DSBs are not random,often cluster-ing at meiotic recombination hot spots(Lichten and Goldman1995).There is a line of evidence that the chromatin modifications are involved in the site lection of meiotic DSBs.vi-siae,methylation of histone3at lysine4(H3K4) coincides with sites of DSBs,and the H3K4 methyltransfera Set1is required for DSB for-mation(Sollier et al.2004;Borde et al.2009).In mammalians,Prdm9,a H3K4methyltransfera with a zincfinger domain,mediates the hot spot lection.The difference in the choice of hot spots among mou strains was attributed to a difference in the amino acid quence within the zincfinger domain(Baudat et al.2010;Parvanov et al.
2010).In humans,the major Prdm9iso-form within the population was predicted and shown to specifically bind the known conn-sus quence enriched near recombination hot spots(Baudat et al.2010;Meyer et al.2010). Furthermore,the allelic differences in the zinc finger domain are correlated to the usages of recombination hot spots in humans.Prdm9is a fast-evolving protein in many animals,includ-ing humans(Oliver et al.2010),and this rapid change is thought to counteract a loss of indi-vidual hot spots becau of biad gene conver-sion during the recombination process(Nicolas et al.1989).
The cond difference is that the recombi-nation partners are mainly homologous chro-mosomes in meiosis,whereas they are mainly sister chromatids in DNA repair during mitotic cycles(Kadyk and Hartwell1992;Bzymek et al.茶文化网
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2010).This homolog bias in meiosis is crucial as recombination among sister chromatids would not be productive in terms of generating diver-sity or forming the chiasma that hold homolo-gous chromo
somes together during metapha I.From studies visiae,the partner choice is thought to be mediated by strand ex-change proteins(RecA homologs),Rad51and Dmc1,which promote the invasion of single-stranded DNA into a double-stranded recom-bination partner.Rad51is expresd both in mitotic cycles and meiosis and,on its own,pro-motes intersister chromatid recombination, whereas the meiosis-specific protein Dmc1,to-gether with Rad51,promotes interhomolog re-combination in meiosis(Cloud et al.2012).In addition,interhomolog recombination is pro-moted in meiosis through suppression of Rad51 by two meiosis-specific factors:the kina com-plex Red1/Hop1/Mek1and the Rad51-inter-acting protein Hed1(Busygina et al.2008;Niu et al.2009).
During recombination,a specific arrange-ment of chromosomes,called a bouquet,has been obrved in a wide variety of organisms (Harper et al.2004).In the bouquet arrange-ment,telomeres are attached to a specific area of the nuclear envelope.In the most well-stud-ied organism,thefission yeast Schizosaccharo-myces pombe,bouquet arrangement was shown to be associated with dynamic movement of the nucleus,which facilitates pairing and recom-bination(Fig.1)(Chikashige et al.1994).Dur-ingfission yeast interpha,the spindle pole body(SPB)is associated with centromeres(Fu-nabiki et al.1993).At the ont of meiosis,the SPB switches its association from centromeres to telomeres(Chikashige et al.1994).SUN and KASH domain proteins,together with Bqt仁寺洞
1and Bqt2,connect telomeres and cytoplasmic aster microtubules,which are organized by the mei-osis-specific SPB protein Hrs1/Mcp6(Saito et al.2005;Tanaka et al.2005;Chikashige et al. 2006).The dynein motor drives the oscillatory movement of the nucleus to facilitate homolo-gous chromosome pairing(Y amamoto et al. 1999).
In C.elegans,the paring center near a telo-mere on each chromosome acts as the initiator of meiotic chromosome paring,and the pair-ing centers also interact with cytoplasmic dy-nein through links of SUN–KASH domain pro-teins,which span the nuclear envelope(Sato et al.2009;Baudrimont et al.2010;Wynne et al. 2012).Movement along the nuclear envelope, mediated by dynein,induces dynamic move-ment of pairing centers.In mou spermato-cytes,bouquet organization and microtubule-dependent nuclear movement were reported during early meiotic propha(Scherthan et al. 1996;Morimoto et al.2012).In addition,in-volvement of SUN–KASH domain proteins has been shown(Morimoto et al.2012).
An interesting example is found -visiae.Vigorous chromosome movement is ob-rved in meiotic propha I(Conrad et al. 2008;Koszul et al.2008).Like other organisms, this chromosome movement is led by telomere cluster near spindle pole bodies,and a SUN domain protein is involved in this movement
Figure1.Bouquet formation and oscillatory nuclear movement infission yeast meiosis.Clustering of telomeres and their linkage to the cytoskeleton enable oscillatory movement of the propha nucleus and facilitate paring of homologous chromosomes.SPB,spindle pole body.
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(Rao et al.2011).Surprisingly,actinfilaments, not microtubules,are responsible for this move-ment(Koszul et al.2008). POSTRECOMBINATION EVENTS Compared with recombination and chromo-some gregation,much less attention has been paid to the period between the two events in meiosis.However,this period is usually longest in meiosis.All mammalian oocytes arrest mei-osis at birth until ovulation.This means that in human oocytes,arrest lasts up to40years.This prolonged arrest is linked to so-called maternal age effect in humans(Hassold and Hunt2009). Maternal age eff
ect is the phenomenon that the incidence of aneuploidy increas as the age of the mothers increas.The cau is still under inten discussion,but cohesin fatigue is one of the attractive hypothes.In mitotic cycles,co-hesin establishes at S pha and the same cohesin complex stays on chromosomes until mitosis (Uhlmann and Nasmyth1998).If there is no new cohesin loading during the meiotic arrest, the same cohesin molecules have to keep chro-matids together for decades.It is hypothesized that gradual loss of cohesin during the pro-longed arrest probably increas the frequency of misgregation.Evidences suggest that cohe-sin does not turn over in mou oocytes once it is established(Revenkova et al.2010;Tachibana-Konwalski et al.2010),and oocytes from old mothers have reduced cohesin on chromosomes in mou(Lister et al.2010).
During the postrecombination period,in some species,a compact cluster of chromo-somes forms in the enlarged nucleus.In Dro-sophila oocytes,the structure was called the kar-yosome and forms soon after the completion of recombination(King1970).Similar clustering of chromatin within the nucleus can be found within mammalian oocytes.In mou oocytes, two types of chromatin organization were found in immature oocytes,which are often referred to as SN(surrounded nucleolus)and NSN (nonsurrounded nucleolus).In a nucleus with SN,meiotic chromosomes are clustered around the nucleolus with centromeres in proximity to the nucleolus.This clustered chromat
in is also referred to as the karyosphere,and is also found in human oocytes(Parfenov et al.1989).In mou,oocytes with an SN configuration are more competent for further development after fertilization than ones with an NSN config-uration(Zuccotti et al.1998,2002).From stud-ies in Drosophila,it is propod that clustering of meiotic chromosomes facilitates formation of one unified spindle(Lancaster et al.2007). As oocytes have a large nucleus and cytoplasm and spindles asmbled around chromosomes without centrosomes,chromosomes distant from each other may form parate spindles. Although chromosome clustering is a wide-spread phenomenon in oocytes,very few mo-lecular studies have,so far,been performed on the molecular basis of this process.In Dro-sophila oocytes,karyosome formation requires the conrved kina NHK-1(Cullen et al. 2005;Ivanovska et al.2005).A study identified barrier-to-autointegration factor(BAF),a link-er protein between chromosomes and the nu-clear envelope,as one of the critical substrates of NHK-1in meiosis(Fig.2)(Lancaster et al. 2007).It is propod that the phosphorylation of BAF by NHK-1is required for relea of chro-matin from the nuclear envelope to allow the karyosome formation.A further study showed that NHK-1activity is suppresd by the mei-otic recombination checkpoint to block nuclear reorganization,including karyosome forma-tion,in respon to unrepaired DSBs(Lancaster et al.2010).
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REDUCTIONAL AND EQUATIONAL CHROMOSOME SEGREGATION Homologous chromosomes are gregated in thefirst meiotic division,and sister chromatids are gregated in the cond division.T o achieve this,two major process are specifically mod-ified in meiosis in comparison with mitosis (Fig.3).
Monopolar Attachment of Sister Chromatids in Meiosis I
Thefirst difference of meiosis from mitosis is the behavior of kinetochores to achieve bipolar
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Recombination state
state
N
Figure2.Formation of the karyosome in Drosophila oocytes.The conrved protein kina NHK-1phosphor-ylates barrier-to-autointegration factor(BAF),a linker between the nuclear envelope and chromatin,to relea meiotic chromosomes from the nuclear envelope.The meiotic recombination checkpoint suppress NHK-1 activity to keep the nucleus in the recombination state when DNA double-strand breaks(DSBs)are still prent.
Mitosis Meiosis
Figure3.Reductional and equational chromosome gregation.Cohesin connects sister chromatids.In mitosis, sister kinetochores are attached to microtubules from the opposite poles.Cohesin connects sister chromatids and the removal of cohesin along chromosomes triggers sister chromatid paration.Homologous chromo-somes behave independently.In meiosis I,sister kinetochores are attached to microtubules from the same pole. Homologous chromosomes are attached to the opposite poles and connected by chiasma.Destruction of cohesin from chromosome arms triggers homologous chromosome paration.Cohesin at centromeres is protected to provide a linkage among sister chromatids.In meiosis II,sister kinetochores are attached to microtubules from the opposite poles.Destruction of the centromeric cohesin triggers sister chromatid pa-ration.
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