|Year : 2015 | Volume
| Issue : 3 | Page : 360-366
The role of sex chromosomes in mammalian germ cell differentiation: can the germ cells carrying X and Y chromosomes differentiate into fertile oocytes?
Department of Surgery, Research Institute of MUHC; Department of Biology; Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada
|Date of Submission||17-Aug-2014|
|Date of Decision||07-Oct-2014|
|Date of Acceptance||08-Oct-2014|
|Date of Web Publication||30-Dec-2014|
Department of Surgery, Research Institute of MUHC; Department of Biology; Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec
Source of Support: None, Conflict of Interest: None
The sexual differentiation of germ cells into spermatozoa or oocytes is strictly regulated by their gonadal environment, testis or ovary, which is determined by the presence or absence of the Y chromosome, respectively. Hence, in normal mammalian development, male germ cells differentiate in the presence of X and Y chromosomes, and female germ cells do so in the presence of two X chromosomes. However, gonadal sex reversal occurs in humans as well as in other mammalian species, and the resultant XX males and XY females can lead healthy lives, except for a complete or partial loss of fertility. Germ cells carrying an abnormal set of sex chromosomes are efficiently eliminated by multilayered surveillance mechanisms in the testis, and also, though more variably, in the ovary. Studying the molecular basis for sex-specific responses to a set of sex chromosomes during gametogenesis will promote our understanding of meiotic processes contributing to the evolution of sex determining mechanisms. This review discusses the fate of germ cells carrying various sex chromosomal compositions in mouse models, the limitation of which may be overcome by recent successes in the differentiation of functional germ cells from embryonic stem cells under experimental conditions.
Keywords: embryonic stem cells; germ cells; oocyte; sex chromosomes; sex reversal
|How to cite this article:|
Taketo T. The role of sex chromosomes in mammalian germ cell differentiation: can the germ cells carrying X and Y chromosomes differentiate into fertile oocytes?. Asian J Androl 2015;17:360-6
|How to cite this URL:|
Taketo T. The role of sex chromosomes in mammalian germ cell differentiation: can the germ cells carrying X and Y chromosomes differentiate into fertile oocytes?. Asian J Androl [serial online] 2015 [cited 2021 Aug 1];17:360-6. Available from: https://www.ajandrology.com/text.asp?2015/17/3/360/143306 - DOI: 10.4103/1008-682X.143306
| Introduction|| |
In mammalian development, gonadal sex, either testis or ovary, is determined by the presence or absence of the Sry gene on the Y chromosome. Subsequently, germ cells undergo sexual differentiation dependent on the gonadal environment. Therefore, spermatogenesis takes place in the presence of X and Y chromosomes, and oogenesis in the presence of two X chromosomes. However, sex reversal occurs at the frequency of 1 in 20 000 newborn boys and is reported less frequently among girls. , In the XX testis, the XX germ cells enter a resting stage, the first phase of spermatogenesis, and become prospermatogonia; however, they are eliminated at the developmental stages during which the prospermatogonia normally resume mitotic activity and initiate differentiation into spermatogonia. By contrast, in the XY ovary, the XY germ cells enter meiosis and continue to differentiate as the primary oocytes, but their fertility depends on species, genetic background, and causes of sex reversal (reviewed by Amleh et al.  ). It has recently been shown that mouse embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) can differentiate into primordial germ cell (PGC)-like cells in culture and then into functional sperm and oocytes after transfer into the testicular and the ovarian somatic environment, respectively. , Given that XX and XY ESCs are available, they can theoretically be differentiated into XX prospermatogonia and XY oocytes. This review summarizes what is known about the role of sex chromosomes in germ cell sex differentiation and functions and discusses the prospect of producing XY oocytes from the ESCs. Most of the discussion is focused on mouse models, which have been best studied as to this aspect; however, human cases are also included where information is available.
| Sex Determination and Differentiation of Gonads|| |
In mammals, a single exon gene SRY on the Y chromosome is activated in the XY gonadal primordium and initiates a cascade of molecular and morphological events leading to testicular differentiation (See reviews ,,, ). SRY-encoded protein (SRY) is a transcription factor containing an HMG-box DNA-binding motif that directly targets SOX9, which encodes another transcription factor sharing the DNA binding motif with SRY. SOX9 upregulates other genes, such as FGF9 and PGD2, which are involved in the differentiation of the Sertoli cells that compose the testis cords. By contrast, in the absence of SRY or SOX9, ovarian differentiation is initiated in the XX gonad without distinct morphological changes by the activation of genes, such as WNT4 and FOXL2, whose protein products antagonize testicular differentiation in gonadal somatic cells (see reviews , ). Follicular structures are formed after germ cells have differentiated into primary oocytes and reached the diplotene stage of the meiotic prophase (see below). More details about the molecular mechanisms regulating testicular and ovarian differentiation are given in the above-mentioned reviews and not repeated here.
| Sexual Differentiation of Germ Cells|| |
The PGCs originate in the proximal epiblast and migrate into a gonadal primordium that is undergoing early sexual differentiation. ,, Parental origin-specific DNA methylation is largely eliminated in the PGCs during this period. ,, The subsequent sexual differentiation of germ cells is regulated by their gonadal environment , ([Figure 1]). In the testis, the PGCs become arrested at the G 0 /G 1 stage of the mitotic cell cycle, undergo male-specific DNA methylation, and resume proliferation after birth.  In the entire male reproductive life, while the population of spermatogonial stem cells continually proliferates, a cohort of spermatogonia enter meiosis and differentiate into haploid spermatozoa in a cyclic manner. In the ovary, most, if not all, PGCs enter meiosis and reach the end of the first meiotic prophase, named the diplotene stage, at 5-7 months of pregnancy in humans or around the day of delivery in the mouse. ,, The diplotene oocytes become surrounded by granulosa cells and together form primordial follicles, which remain at this stage as an oocyte reserve until they are recruited into follicular growth. ,, This resting stage can last for decades in humans or months in mice. Female-specific DNA methylation takes place in oocytes during the growth phase. ,,, Fully-grown oocytes resume the meiotic cell cycle and divide into haploid oocytes upon ovulation and fertilization. Thus, germ cells of both sexes enter meiosis to become haploid, but at very different stages of life and in different manners. It has been shown that the entry of germ cells into meiosis is regulated by local signaling from the surrounding somatic cells, and can be manipulated by pharmacological or genetic modifications ,,,,,, ([Figure 1]). Another distinct difference between the two sexes is the ability of germ cells to proliferate continuously; female germ cells cease proliferation when they enter meiosis in fetal ovaries. Hence, a female has a finite number of oocytes in reserve, and her reproductive life ends when her oocyte reserve decreases below the threshold that is required for sustaining ovarian functions.
|Figure 1: Sexual differentiation of germ cells. ICM: innercell mass; ESC: embryonic stem cells; EpiC: epiblast cells; PGC: primordial germ cells; MPI: meiotic prophase I.|
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| Differentiation of Sperm and Eggs From Embryonic Stem Cells|| |
Since the first reports in 2003, , numerous attempts have been made to differentiate ESCs into germ cells, and eventually into mature haploid gametes that have the capacity to produce normal offspring (see reviews , ). PGC-like cells appear spontaneously when murine and human ESCs are cultured under various conditions. ,,,,, However, most attempts result in a failure to generate functional gametes; the major obstacle appears to be a lack of proper meiotic events in the nucleus.  Although meiosis is central to normal gametogenesis, it has been reported that "oocyte-like" cells can differentiate in the absence of meiosis,  and ultimately, the production of offspring is the only reliable evidence for functional gametes. The first success in obtaining the birth of live offspring from ESC-derived male haploid cells was reported in 2006.  The key to this success may be the selection of ESCs expressing STRA8, which is essential for the initiation of meiosis. , However, the resultant pups showed growth abnormalities with incorrect DNA methylation profiles, and most died within the first month of life.
Hayashi et al.  have achieved a step-by-step induction of XY ESCs into epiblast-like cells and then into PGC-like cells with high efficiency ([Figure 1]). After these PGC-like cells had been dissociated into single cells and transplanted into germ cell-deficient mouse testes, they colonized the host seminiferous tubules and differentiated into spermatozoa-like cells, which produced healthy and fertile offspring of both sexes. Enrichment of donor cells based on the genes that they expressed not only increased the efficiency of gamete derivation but also prevented the development of teratomas in the host testis. When the PGC-like cells derived from XX ESCs by the same protocol had been aggregated with fetal ovarian somatic cells to form reconstituted ovaries in vitro and transplanted into the ovarian bursa or kidney subcapsular site of recipient mice, growing follicles containing oocyte-like cells were obtained.  When these oocyte-like cells were allowed to mature and were fertilized in vitro, they developed into blastocyst-stage embryos. After fertilized eggs had been transferred into foster females, healthy and fertile offspring of both sexes was generated. These findings indicate that ESCs can be induced to differentiate into PGCs under defined in vitro conditions, but also that their sexual differentiation into spermatozoa and oocytes depends on their testicular and ovarian somatic environment, respectively. However, the efficiency of healthy offspring production from ESCs is still limited, particularly through the female germ-line and similar attempts starting with iPSCs of embryonic fibroblast origin yielded much less success. , We still poorly understand whether certain oocytes are eliminated during the meiotic prophase (see below), excluded from follicular recruitment or eliminated by follicular atresia under physiological conditions. Circumventing the normal surveillance mechanism due to artificial conditions may decrease the proportion of oocytes that are competent for embryonic development.
| Sex Chromosomes in Embryonic Stem Cells|| |
In early studies, oocyte-like cells were generated from ESC lines that had been established from 129SY male mouse embryos, which are inevitably of the XY karyotype. , None of these attempts succeeded in producing functional oocytes. It has been reported that when germ-cell-like cells were derived from human ESCs of either XX or XY origin, their gene expression profiles indicated that both male and female programs, namely the expression of TEKT1 and GDF9 respectively, were activated regardless of karyotype.  Using a very different protocol, differentiation of haploid cells with male germ-line gene expression patterns was obtained from human iPSCs (but not ESCs) of either XX or XY origin.  These observations suggest the bidirectional potential of ESCs regardless of their chromosomal sex. However, the only successful derivation of functional oocytes so far used mouse XX ESCs.  It remains to be evaluated whether the PGC-like cells derived from XY ESCs can differentiate into functional oocytes in the ovarian environment. A caveat is the stability of the sex chromosomes in ESCs and iPSCs. It has been reported that both XX and XY human ESCs tend to lose the second sex chromosome to become XO at high frequencies (3.0% and 1.5%, respectively) after multiple passages in culture.  Therefore, the karyotype in the initial cell line does not warrant its maintenance during gametogenesis.
| Role of Sex Chromosomes in Spermatogenesis|| |
In XX sex-reversed males, the XX germ cells enter the early phase of spermatogenesis and become arrested, but do not survive to resume the mitotic cell cycle. It has been established that the presence of the second X chromosome is incompatible with spermatogenesis since XO germ cells lacking the second X chromosome survive to initiate spermatogonial proliferation (reviewed by Burgoyne  ). However, these cells do not complete spermatogonial proliferation and differentiation, and thus fail to enter meiosis. In mice and men, deletions of specific regions of the Y chromosome have been linked to an early failure of spermatogenesis and consequent sterility. ,,,, In the mouse, deletion mapping of the Y chromosome located a gene necessary for spermatogonial proliferation to a 1.3 Mb deletion on the short arm (Yp) that removed six single copy genes and created a Zfy2/1 fusion gene; subsequent Y transgene additions identified Eif2s3y as the spermatogonial proliferation gene.  Some genes on the mouse long arm (Yq) such as Sly are required for postmeiotic gene expression and morphological differentiation of spermatozoa.  However, the problems associated with late spermatogenesis can be circumvented either by intracytoplasmic sperm injection or by round spermatid injection (ROSI) into the oocytes, to produce live offspring. , Using the ROSI technique, the Eif2s3y gene alone was shown to be sufficient to allow for the production of live offspring when added to an XOSry male mouse. , The encoded EIF2S3Y protein is the third subunit of the eukaryotic translation initiation factor 2, which is ubiquitously expressed, but plays a specific role in spermatogonial proliferation in the testis. Its X homolog Eif2s3x is also ubiquitously expressed, and its protein shares biological activity with EIF2S3Y. Accordingly, it has been proposed that the maintenance of a double EIF2S3 dose affords a selective advantage in both sexes since Eif2s3x is one of only a few mouse X-linked genes known to escape X inactivation.  Although Eif2s3y is not conserved in any of the simian primates, including humans, the human Y chromosome harbors EIF1AY, a Y-encoded version of the elongation and initiation factor EIF1A. The caveat is that the spermatids generated by Eif2s3 expression without any other Y-linked genes but Sry often contain diploid, instead of haploid, DNA contents, and their success in offspring production is limited.  The lack of a pairing partner for the X chromosome was initially suspected to be the cause of low fertility,  but overcoming X chromosome univalence by providing its pairing partner did not improve meiotic arrest or increase ROSI success,  suggesting that other Y-linked genes might also be required for obtaining spermatids that are fully functional in ROSI. It has recently been established that mouse Zfy1 and Zfy2 (encoding zinc finger transcription factors) are required for promoting the second meiotic division in spermatocytes, thus generating haploid spermatids. 
| Role of Sex Chromosomes in Oogenesis|| |
In the normal ovary, the germ cells carry two X chromosomes. The second X chromosome is initially inactivated as in any somatic cells, but gradually reactivated prior to the onset of meiosis. ,, Hence, the oocyte develops in the presence of two transcriptionally active X chromosomes for the rest of its reproductive life. Consequently, the absence of the second X chromosome from the XO oocyte may be disadvantageous when compared to its presence in the XX oocyte. Anomalies of XO females in humans are known as Turners syndrome (TS). Ninety-nine percentage of XO fetuses die in the womb, and TS girls who have been born develop short stature, congenital cardiovascular defects, and metabolic abnormalities. , In addition, most TS women are infertile due to the early loss of oocytes. ,, By contrast, XO female mice are viable, healthy, and fertile.  Since the X chromosome is subjected to genomic imprinting during gametogenesis, XO female mice carrying paternal X chromosomes show more severe phenotypes than are expected from the mere half-dosage of X chromosome contents. ,,, Nonetheless, they can be fertile, and their counterparts, XO females carrying maternal X chromosomes, are quite normal. The striking difference between humans and mice with the XO karyotype has been explained by the fact that many fewer X-linked genes escape X inactivation in the mouse as compared to humans; 15% of X-linked genes consistently escape X inactivation, and a further 10% escape in certain tissues or individuals in humans, whereas only 3.3% of X-linked genes escape X inactivation in the mouse. ,, Therefore, it has been assumed that the absence of the second X chromosome can be detrimental in humans, but less so in mice. However, it was recently proposed that human XO embryos may die due to a haplodeficiency of placental gene expression.  If this hypothesis is correct, the early loss of XO oocytes may be a consequence of placental defects, and they may survive and become functional if they have been placed in a healthier environment.
Anomalies of XY females in humans are known as Swyer syndrome. ,, Fifteen to twenty percentages of XY sex reversal can be attributed to SRY mutations, including point mutations, frame-shifts and deletions. ,, In addition, XY females may develop as a consequence of gonadal dysgenesis, a failure in gonadal differentiation, because female phenotype is a default pathway. XY women are infertile due to the absence of oocytes although exceptional fertile cases have been reported.  Around 30% of all XY females and 60% of familial cases of XY sex-reversed individuals are reported to develop gonadoblastom. ,,,, Therefore, gonads are surgically removed in most cases of XY sex reversal when identified. Donor oocytes are the only option for these women in order to conceive babies. ,
In the mouse, in addition to Sry, over ten genes have been identified to play critical roles in testicular differentiation; their functional deletion results in sex reversal in the XY gonad (see reviews ,,, ). However, complete sex reversal by autosomal gene mutations is rare since the XY ovary develops only when testicular components are absent or limited to a small proportion. , In other words, sex reversal must be nearly complete in order to develop XY ovaries. Therefore, XY female mouse models for studying the influence of the Y chromosome on female fertility are limited to those with impaired SRY functions. One exception is the XY female mouse, whose sex has been reversed by a conditional deletion of SOX9 from gonadal somatic cells while the Sry gene remains intact.  The fertility of XY female mice depends on the cause of sex reversal as well as the genetic background ([Table 1]). When sex reversal is caused by the deletion of the Y chromosome region harbouring Sry, the resultant XYTdym1 female on a mixed genetic background has severely reduced fertility; nonetheless, it occasionally produces offspring.  Better fertility was reported for the XYTdym1 female on the outbred MF1 background after being delivered by XXYTdym1 females.  By contrast, when most copies of Rbmy repeats on the Y chromosome are deleted but Sry remains intact, Sry is repressed during gonadal differentiation and sex reversal ensues. On an MF1 background, these XYd females are nearly as fertile as XO females.  This difference in female fertility has recently been attributed to the expression versus repression of the Y-linked Zfy2 gene.  In XY females of the B6.Y TIR or B6.Y POS strain, the Sry gene is intact and expressed during gonadal differentiation and yet fails to initiate testicular differentiation. ,, These XY females are sterile except for one litter at an early stage of backcross generation. , Similarly to XYTdym1 females, XY females with a conditional deletion of SOX9 are subfertile, occasionally producing offspring.  Thus, the physical presence of the Y chromosome does not prevent female fertility, but the configuration or expression of genes on the Y chromosome appears to critically influence female fertility.
| Infertility of The B6.Y TIR Female Mouse|| |
Our laboratory has been particularly interested in the infertility of XY oocytes in the B6.Y TIR female mouse since they carry intact X and Y chromosomes. Their male siblings that have developed testes are fertile. Therefore, this mouse model provides a unique opportunity for comparing spermatogenesis and oogenesis under identical chromosomal compositions. We have reported that more than half of B6.Y TIR gonads develop into ovaries, in which germ cells enter meiosis and go through the meiotic prophase. ,, The X and Y chromosomes do not pair in most XY oocytes during the first meiotic prophase, unlike in XY spermatocytes ([Figure 2]). Subsequently, a greater number of XY oocytes are eliminated by the end of meiotic prophase, compared to XX oocytes, which can be attributed to a surveillance mechanism of chromosome asynapsis (described later). Nonetheless, a considerable number of XY oocytes survive to reach the diplotene stage and form follicles. The XY ovary contains follicles at all stages at young ages, but rapidly loses its oocytes with age, and retains no, or very few, oocytes/follicles at 2 months after birth.  When XY fully-grown oocytes are subjected to meiotic resumption and maturation by in vitro culture, the unpaired X and Y chromosomes are segregated independently. , However, their distribution is not random; 70% of MII-oocytes retain single sex chromosomes, equally X or Y, 24% retain both X and Y, and the rest retain none. Regardless, very few MII-oocytes reach the two-cell stage or beyond after fertilization, thus diminishing the chance for reproduction.
|Figure 2: Pairing of sex chromosomes at the pachytene stage of meiotic prophase I. Microspread ovarian or testicular cells were immunostained with human autoantibody CREST (red), with specific antibodies against SCP3 (red) and γH2AX (green), and counterstained with DAPI (blue). The merged image (top) is followed by γH2AX signals alone (middle) and red signals of SCP3 and CREST alone (bottom). ( a ) A pachytene oocyte nucleus collected from an XX fetal ovary at 18.5 dpc. 20 sets of homologous chromosomes including the XX pair are fully synapsed. No γH2AX signals are seen. ( b ) A pachytene oocyte nucleus collected from a B6.YTIR fetal ovary at 18.5 dpc. The short Y chromosome is apart from the single X chromosome, the latter of which is covered by a γH2AX domain, a characteristic of unsynapsed chromosome. Nineteen autosomal pairs are fully synapsed without γH2AX signals. ( c ) A pachytene spermatocyte nucleus collected from a B6.YTIR adult testis. The X and Y chromosomes are partially synapsed at their pseudoautosomal regions and covered by a γH2AX domain, named XY or sex body. Nineteen autosomal pairs are fully synapsed.|
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The developmental incompetence of the oocytes from XY females can be attributed to their cytoplasmic defects; when the nuclei of XY oocytes have been transferred into enucleated XX oocytes, either at the GV- or MII-stage, the reconstructed oocytes generate healthy offspring after in vitro fertilisation and embryo transfer.  The offspring faithfully inherit the sex chromosomes identified in the MII-oocytes from XY females except for the death of YY and YO embryos. , It appears that sex chromosome aneuploidy per se does not block oogenesis or embryonic development. We compared gene expression profiles in fully-grown oocytes collected from XX, XO, and XY ovaries.  We found that all the genes tested showed comparable transcript levels between XX and XO oocytes, indicating that the storage of mRNAs is well-adjusted in these oocytes despite the difference in X chromosome numbers. In contrast, many X-linked and autosomal genes showed higher or lower transcript levels in XY oocytes, suggesting that mRNA storage is altered. Many of these differentially expressed genes are also included in the gene expression profile of those XO oocytes which carry a Y-linked Zfy2 transgene, despite their different genetic backgrounds.  mRNA-profile differences may contribute to the fertility of XO oocytes and the infertility of XY and XOZfy2 oocytes.
| Surveillance Mechanism of Germ Cells|| |
In attempts to produce functional gametes ex vivo, it is important to consider the presence of a surveillance mechanism by which a large population of gametes is eliminated under normal physiological conditions. A target of the surveillance mechanism can be a failure in chromosome synapsis, which would otherwise lead to aneuploidy, the major cause of embryonic loss. Chromosome asynapsis, irrespective of the underlying cause, is almost always associated with spermatogenic arrest at the mid-pachytene stage of the meiotic prophase or at the metaphase stage of the first meiotic division, resulting in subfertility or sterility in males (see reviews , ). A "pachytene checkpoint" has been proposed as a mechanism to eliminate the meiocytes with synaptic defects in Saccharomyces cerevisiae,  and this hypothesis has been adapted to mammals. , However, whether an analogous checkpoint operates in mammalian gametogenesis remains to be verified. One major issue is the sex difference; various mutations that affect meiotic synapsis block spermatogenesis but not oogenesis during the first meiotic prophase (reviewed by Morelli and Cohen  ). If the pachytene checkpoint mechanism has been conserved from yeast to mammals, it is difficult to explain its inefficiency in the mammalian female germ-line.
An alternative hypothesis accommodates the sex difference; a surveillance mechanism may have evolved to cooperate with the presence of X and Y chromosomes in the spermatocyte, deviating from that in the oocyte. The mammalian X and Y chromosomes have poor homology except for the small pseudoautosomal region (PAR). Yet, their pairing and recombination is obligatory for successful spermatogenesis.  This is achieved by the formation of the XY or sex body to accommodate X and Y chromosomes and facilitate their pairing at their PARs. However, the remaining parts of the X and Y chromosomes become separated, showing all the characteristics of unsynapsed chromosomes, such as accumulations of ART, BRCA1, and phosphorylated histone variant H2AX (gH2AX) ,,,, ([Figure 2]). A pachytene checkpoint, if it exists, would recognize the X-Y asynapsis and block spermatogenesis. Instead, both the X and Y chromosomes are subjected to transcriptional silencing, named meiotic sex chromosome inactivation (MSCI), and processed in the XY body differentially from the autosomal pairs. ,, Overall transcriptional activity is suppressed at the premeiotic S-phase and resumes in the autosomes prior to the pachytene stage in the normal gametogenesis. Therefore, the transcriptional repression of the X and Y chromosomes throughout the pachytene stage is distinct. Evidence has accumulated to prove that MSCI is obligatory for spermatogenesis, and also that interference with MSCI results in unwanted expression of X and Y-linked genes and subsequent loss of mid-pachytene spermatocytes. , Asynapsis of the autosomes, which occurs naturally or is caused by gene mutations, often interferes with X-Y pairing and MSCI, leading to spermatogenesis arrest. ,, It has recently been reported that misexpression of Y-linked Zfy1/Zfy2 is sufficient to arrest pachytene spermatocytes. 
The normal oocyte carries two X chromosomes, which pair efficiently like autosomal pairs and do not need MSCI. Nonetheless, the majority (70%) of oocytes is eliminated during the first meiotic prophase in normal ovarian development. ,, The cause or mechanism of this major oocyte loss is not well understood. However, evidence is accumulating to support the presence of a surveillance mechanism during this period. First, apoptosis, a common form of "programmed cell death," plays a major role in oocyte elimination; a deficiency in caspase 9, a key player in the mitochondrial apoptotic pathway, prevents oocyte loss during the first meiotic prophase.  Remarkably, caspase 9 and its upstream apoptotic pathway are constitutively activated in all oocytes; therefore, oocytes must be protected from apoptotic execution until they are destined for such a fate  (Chung and Taketo, unpublished results). Second, when the pairing partner for the single X chromosome is absent, such as in XO and XY oocytes, greater numbers of oocytes are eliminated by the end of the first meiotic prophase as compared to XX oocytes. ,, The pachytene checkpoint hypothesis cannot explain this oocyte loss since sufficient numbers of XO and XY oocytes survive through the first meiotic prophase to produce mature oocytes and make XO females fertile, although XY females encounter other infertility problems.
An alternative hypothesis, meiotic silencing of unsynapsed chromatin (MSUC), shares many aspects of molecular mechanisms with MSCI in the spermatocyte but acts less stringently. ,, It has been proposed that the single X chromosome is subjected to MSUC in XO oocytes, resulting in their elimination, but it occasionally synapses within self, or with the autosomes, and escapes from the MSUC response, resulting in oocyte survival. ,, However, the low frequency of X chromosome self-synapsis does not explain the number of XO oocytes that survive. Moreover, we found that the consequence of MSUC, based on the localization of X-encoded ATRX, is heterogeneous in XY oocytes.  We hypothesize that the MSUC response in oocytes is variable because the first meiotic prophase, particularly at the pachytene stage, is very short in oocytes compared to spermatocytes (2 vs 7 days), leaving the interval between transcriptional activation and the MSUC response too short to give a consistent result. Consequently, oocyte survival may depend on the levels and repertoire of essential gene products. These studies are limited to sex chromosomes while normal oocytes may have a synaptic failure in any chromosomes.  Whether the MSUC hypothesis is applicable to autosomal asynapsis in oocytes remains to be evaluated.
| Concluding Remarks|| |
It is possible to obtain XY oocytes carrying intact X and Y chromosomes as a consequence of sex reversal in the mouse. However, such a mouse is available only with a Y chromosome of a specific origin on a certain genetic background. Hence, functionality of XY oocytes has not yet been vigorously examined due to the limited availability of sex-reversed mouse models. It must be noted that sex reversal results in functional gametes in some rodent and nonmammalian invertebrate species. ,, It is important to know whether or not mammals have evolved mechanisms to prevent the reproduction of sex-reversed individuals. Furthermore, the XY oocyte becomes infertile or subfertile largely due to the expression of Y-linked gene (s) leading to ooplasmic defects in a mouse model. Such defects can be prevented by genetic or nongenetic manipulation of oocytes during culture. An understanding of the role of sex chromosomes in germ cell differentiation and functions will be promoted by deriving XY oocytes from XY ESCs on more diverse genetic backgrounds.
| Acknowledgments|| |
I thank current and past members of TT laboratory for contributing to our papers cited in this review. I am also grateful to Drs. Paul Burgoyne and Y-F Chris Lau for their comments and valuable advices during this manuscript preparation. Our research has been supported by CIHR and NSERC grants to TT.
| Competing Interests|| |
The authors declare that they have no competing interests.
| References|| |
de la Chapelle A. The etiology of maleness in XX men. Hum Genet
1981; 58: 105-16.
German J, Simpson JL, Chaganti RS, Summitt RL, Reid LB, et al
. Genetically determined sex-reversal in 46, XY humans. Science
1978; 202: 53-6.
Amleh A, Xu BZ, Taketo T. Role of sex chromosomes in mammalian female fertility. In: D'Aguino M, Stallon V, editors. Sex Chromosomes: new Research. New York: Nova Science; 2013. p. 53-86.
Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M. Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell
2011; 146: 519-32.
Hayashi K, Ogushi S, Kurimoto K, Shimamoto S, Ohta H, et al
. Offspring from oocytes derived from in vitro
primordial germ cell-like cells in mice. Science
2012; 338: 971-5.
Brennan J, Capel B. One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet
2004; 5: 509-21.
Kashimada K, Koopman P. Sry: the master switch in mammalian sex determination. Development
2010; 137: 3921-30.
Park SY, Jameson JL. Minireview: transcriptional regulation of gonadal development and differentiation. Endocrinology
2005; 146: 1035-42.
Sekido R, Lovell-Badge R. Sex determination and SRY: down to a wink and a nudge? Trends Genet
2009; 25: 19-29.
Kim Y, Capel B. Balancing the bipotential gonad between alternative organ fates: a new perspective on an old problem. Dev Dyn
2006; 235: 2292-300.
Schlessinger D, Garcia-Ortiz JE, Forabosco A, Uda M, Crisponi L, et al
. Determination and stability of gonadal sex. J Androl
2010; 31: 16-25.
Lawson KA, Dunn NR, Roelen BA, Zeinstra LM, Davis AM, et al.
Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev
1999; 13: 424-36.
Molyneaux KA, Stallock J, Schaible K, Wylie C. Time-lapse analysis of living mouse germ cell migration. Dev Biol
2001; 240: 488-98.
Tam PP, Zhou SX. The allocation of epiblast cells to ectodermal and germ-line lineages is influenced by the position of the cells in the gastrulating mouse embryo. Dev Biol
1996; 178: 124-32.
Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, et al.
Epigenetic reprogramming in mouse primordial germ cells. Mech Dev
2002; 117: 15-23.
Kato Y, Rideout WM 3 rd
, Hilton K, Barton SC, Tsunoda Y, et al
. Developmental potential of mouse primordial germ cells. Development
1999; 126: 1823-32.
Lee J, Inoue K, Ono R, Ogonuki N, Kohda T, et al.
Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development
2002; 129: 1807-17.
Durcova-Hills G, Hajkova P, Sullivan S, Barton S, Surani MA, et al
. Influence of sex chromosome constitution on the genomic imprinting of germ cells. Proc Natl Acad Sci U S A
2006; 103: 11184-8.
McLaren A. Somatic and germ-cell sex in mammals. Philos Trans R Soc Lond B Biol Sci
1988; 322: 3-9.
Davis TL, Yang GJ, McCarrey JR, Bartolomei MS. The H19 methylation imprint is erased and re-established differentially on the parental alleles during male germ cell development. Hum Mol Genet
2000; 9: 2885-94.
Baker TG. A quantitative and cytological study of germ cells in human ovaries. Proc R Soc Lond B Biol Sci
1963; 158: 417-33.
Borum K. Oogenesis in the mouse. A study of the meiotic prophase. Exp Cell Res
1961; 24: 495-507.
Speed RM. Meiosis in the foetal mouse ovary. I. An analysis at the light microscope level using surface-spreading. Chromosoma
1982; 85: 427-37.
Bristol-Gould SK, Kreeger PK, Selkirk CG, Kilen SM, Cook RW, et al.
Postnatal regulation of germ cells by activin: the establishment of the initial follicle pool. Dev Biol
2006; 298: 132-48.
Liu K, Rajareddy S, Liu L, Jagarlamudi K, Boman K, et al.
Control of mammalian oocyte growth and early follicular development by the oocyte PI3 kinase pathway: new roles for an old timer. Dev Biol
2006; 299: 1-11.
Reddy P, Zheng W, Liu K. Mechanisms maintaining the dormancy and survival of mammalian primordial follicles. Trends Endocrinol Metab
2010; 21: 96-103.
Lucifero D, Mann MR, Bartolomei MS, Trasler JM. Gene-specific timing and epigenetic memory in oocyte imprinting. Hum Mol Genet
2004; 13: 839-49.
Obata Y, Hiura H, Fukuda A, Komiyama J, Hatada I, et al
. Epigenetically immature oocytes lead to loss of imprinting during embryogenesis. J Reprod Dev
2011; 57: 327-34.
Tomizawa S, Kobayashi H, Watanabe T, Andrews S, Hata K, et al.
Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes. Development
2011; 138: 811-20.
Khoueiry R, Ibala-Rhomdane S, Méry L, Blachère T, Guérin JF, et al.
Dynamic CpG methylation of the KCNQ1OT1 gene during maturation of human oocytes. J Med Genet
2008; 45: 583-8.
Bowles J, Knight D, Smith C, Wilhelm D, Richman J, et al.
Retinoid signaling determines germ cell fate in mice. Science
2006; 312: 596-600.
Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, et al
. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci U S A
2006; 103: 2474-9.
Anderson EL, Baltus AE, Roepers-Gajadien HL, Hassold TJ, de Rooij DG, et al.
Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Proc Natl Acad Sci U S A
2008; 105: 14976-80.
Mark M, Jacobs H, Oulad-Abdelghani M, Dennefeld C, Féret B, et al.
STRA8-deficient spermatocytes initiate, but fail to complete, meiosis and undergo premature chromosome condensation. J Cell Sci
2008; 121: 3233-42.
Le Bouffant R, Guerquin MJ, Duquenne C, Frydman N, Coffigny H, et al.
Meiosis initiation in the human ovary requires intrinsic retinoic acid synthesis. Hum Reprod
2010; 25: 2579-90.
Zhou Q, Nie R, Li Y, Friel P, Mitchell D, et al.
Expression of stimulated by retinoic acid gene 8 (Stra8) in spermatogenic cells induced by retinoic acid: an in vivo
study in vitamin A-sufficient postnatal murine testes. Biol Reprod
2008; 79: 35-42.
Ohta K, Lin Y, Hogg N, Yamamoto M, Yamazaki Y. Direct effects of retinoic acid on entry of fetal male germ cells into meiosis in mice. Biol Reprod
2010; 83: 1056-63.
Hübner K, Fuhrmann G, Christenson LK, Kehler J, Reinbold R, et al.
Derivation of oocytes from mouse embryonic stem cells. Science
2003; 300: 1251-6.
Toyooka Y, Tsunekawa N, Akasu R, Noce T. Embryonic stem cells can form germ cells in vitro
. Proc Natl Acad Sci U S A
2003; 100: 11457-62.
Daley GQ. Gametes from embryonic stem cells: a cup half empty or half full? Science
2007; 316: 409-10.
Marques-Mari AI, Lacham-Kaplan O, Medrano JV, Pellicer A, Simón C. Differentiation of germ cells and gametes from stem cells. Hum Reprod Update
2009; 15: 379-90.
Nayernia K, Nolte J, Michelmann HW, Lee JH, Rathsack K, et al. In vitro
-differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev Cell
2006; 11: 125-32.
Qing T, Shi Y, Qin H, Ye X, Wei W, et al.
Induction of oocyte-like cells from mouse embryonic stem cells by co-culture with ovarian granulosa cells. Differentiation
2007; 75: 902-11.
Clark AT, Bodnar MS, Fox M, Rodriquez RT, Abeyta MJ, et al.
Spontaneous differentiation of germ cells from human embryonic stem cells in vitro
. Hum Mol Genet
2004; 13: 727-39.
Geijsen N, Horoschak M, Kim K, Gribnau J, Eggan K, et al
. Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature
2004; 427: 148-54.
Novak I, Lightfoot DA, Wang H, Eriksson A, Mahdy E, et al
. Mouse embryonic stem cells form follicle-like ovarian structures but do not progress through meiosis. Stem Cells
2006; 24: 1931-6.
Dokshin GA, Baltus AE, Eppig JJ, Page DC. Oocyte differentiation is genetically dissociable from meiosis in mice. Nat Genet
2013; 45: 877-83.
Eguizabal C, Montserrat N, Vassena R, Barragan M, Garreta E, et al.
Complete meiosis from human induced pluripotent stem cells. Stem Cells
2011; 29: 1186-95.
Urbach A, Benvenisty N. Studying early lethality of 45, XO (Turner's syndrome) embryos using human embryonic stem cells. PLoS One
2009; 4: e4175.
Burgoyne PS. The role of the mammalian Y chromosome in spermatogenesis. Development
1987; 101 Suppl: 133-41.
Bardoni B, Zuffardi O, Guioli S, Ballabio A, Simi P, et al.
A deletion map of the human Yq11 region: implications for the evolution of the Y chromosome and tentative mapping of a locus involved in spermatogenesis. Genomics
1991; 11: 443-51.
Ma K, Sharkey A, Kirsch S, Vogt P, Keil R, et al.
Towards the molecular localisation of the AZF locus: mapping of microdeletions in azoospermic men within 14 subintervals of interval 6 of the human Y chromosome. Hum Mol Genet
1992; 1: 29-33.
Mahadevaiah SK, Odorisio T, Elliott DJ, Rattigan A, Szot M, et al.
Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spermatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities. Hum Mol Genet
1998; 7: 715-27.
Mazeyrat S, Saut N, Grigoriev V, Mahadevaiah SK, Ojarikre OA, et al.
A Y-encoded subunit of the translation initiation factor Eif2 is essential for mouse spermatogenesis. Nat Genet
2001; 29: 49-53.
Vogt PH, Edelmann A, Kirsch S, Henegariu O, Hirschmann P, et al.
Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet
1996; 5: 933-43.
Cocquet J, Ellis PJ, Yamauchi Y, Mahadevaiah SK, Affara NA, et al.
The multicopy gene Sly represses the sex chromosomes in the male mouse germline after meiosis. PLoS Biol
2009; 7: e1000244.
Yamauchi Y, Riel JM, Wong SJ, Ojarikre OA, Burgoyne PS, et al
. Live offspring from mice lacking the Y chromosome long arm gene complement. Biol Reprod
2009; 81: 353-61.
Yamauchi Y, Riel JM, Stoytcheva Z, Ward MA. Two Y genes can replace the entire Y chromosome for assisted reproduction in the mouse. Science
2014; 343: 69-72.
Ehrmann IE, Ellis PS, Mazeyrat S, Duthie S, Brockdorff N, et al.
Characterization of genes encoding translation initiation factor eIF-2gamma in mouse and human: sex chromosome localization, escape from X-inactivation and evolution. Hum Mol Genet
1998; 7: 1725-37.
Vernet N, Mahadevaiah SK, Yamauchi Y, Decarpentrie F, Mitchell MJ, et al.
Mouse Y-linked Zfy1 and Zfy2 are expressed during the male-specific interphase between meiosis I and meiosis II and promote the 2 nd
meiotic division. PLoS Genet
2014; 10: e1004444.
Chuva de Sousa Lopes SM, Hayashi K, Shovlin TC, Mifsud W, Surani MA, et al
. X chromosome activity in mouse XX primordial germ cells. PLoS Genet
2008; 4: e30.
Monk M, McLaren A. X-chromosome activity in foetal germ cells of the mouse. J Embryol Exp Morphol
1981; 63: 75-84.
Sugimoto M, Abe K. X chromosome reactivation initiates in nascent primordial germ cells in mice. PLoS Genet
2007; 3: e116.
Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet
1991; 87: 81-3.
Stratakis CA, Rennert OM. Turner syndrome an update. Endocrinologists
2005; 15: 27-36.
Borgström B, Hreinsson J, Rasmussen C, Sheikhi M, Fried G, et al.
Fertility preservation in girls with Turner syndrome: prognostic signs of the presence of ovarian follicles. J Clin Endocrinol Metab
2009; 94: 74-80.
Hreinsson JG, Otala M, Fridström M, Borgström B, Rasmussen C, et al.
Follicles are found in the ovaries of adolescent girls with Turner's syndrome. J Clin Endocrinol Metab
2002; 87: 3618-23.
Modi DN, Sane S, Bhartiya D. Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads. Mol Hum Reprod
2003; 9: 219-25.
Cattanach BM. XO mice. Genet Res Camb
1962; 3: 487-90.
Hunt PA. Survival of XO mouse fetuses: effect of parental origin of the X chromosome or uterine environment? Development
1991; 111: 1137-41.
Jamieson RV, Tan SS, Tam PP. Retarded postimplantation development of X0 mouse embryos: impact of the parental origin of the monosomic X chromosome. Dev Biol
1998; 201: 13-25.
Okamoto I, Otte AP, Allis CD, Reinberg D, Heard E. Epigenetic dynamics of imprinted X inactivation during early mouse development. Science
2004; 303: 644-9.
Burgoyne PS, Baker TG. Perinatal oocyte loss in XO mice and its implications for the aetiology of gonadal dysgenesis in XO women. J Reprod Fertil
1985; 75: 633-45.
Fisher EM, Beer-Romero P, Brown LG, Ridley A, McNeil JA, et al.
Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome. Cell
1990; 63: 1205-18.
Yang F, Babak T, Shendure J, Disteche CM. Global survey of escape from X inactivation by RNA-sequencing in mouse. Genome Res
2010; 20: 614-22.
Prothero KE, Stahl JM, Carrel L. Dosage compensation and gene expression on the mammalian X chromosome: one plus one does not always equal two. Chromosome Res
2009; 17: 637-48.
Behzadian MA, Tho SP, McDonough PG. The presence of the testicular determining sequence, SRY, in 46, XY females with gonadal dysgenesis (Swyer syndrome). Am J Obstet Gynecol
1991; 165: 1887-90.
Simpson JL, Blagowidow N, Martin AO. XY gonadal dysgenesis: genetic heterogeneity based upon clinical observations, H-Y antigen status and segregation analysis. Hum Genet
1981; 58: 91-7.
Cameron FJ, Sinclair AH. Mutations in SRY and SOX9: testis-determining genes. Hum Mutat
1997; 9: 388-95.
Jäger RJ, Anvret M, Hall K, Scherer G. A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature
1990; 348: 452-4.
Lim HN, Freestone SH, Romero D, Kwok C, Hughes IA, et al
. Candidate genes in complete and partial XY sex reversal: mutation analysis of SRY, SRY-related genes and FTZ-F1. Mol Cell Endocrinol
1998; 140: 51-8.
Tulic I, Tulic L, Micic J. Pregnancy in patient with Swyer syndrome. Fertil Steril
2011; 95: 1789.e1-2.
Bernstein R, Jenkins T, Dawson B, Wagner J, Dewald G, et al.
Female phenotype and multiple abnormalities in sibs with a Y chromosome and partial X chromosome duplication: H-Y antigen and Xg blood group findings. J Med Genet
1980; 17: 291-300.
Lau YF. Gonadoblastoma, testicular and prostate cancers, and the TSPY gene. Am J Hum Genet
1999; 64: 921-7.
Manuel M, Katayama PK, Jones HW Jr. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol
1976; 124: 293-300.
Uehara S, Funato T, Yaegashi N, Suziki H, Sato J, et al.
SRY mutation and tumor formation on the gonads of XP pure gonadal dysgenesis patients. Cancer Genet Cytogenet
1999; 113: 78-84.
Verp MS, Simpson JL. Abnormal sexual differentiation and neoplasia. Cancer Genet Cytogenet
1987; 25: 191-218.
Frydman R, Parneix I, Fries N, Testart J, Raymond JP, et al
. Pregnancy in a 46, XY patient. Fertil Steril
1988; 50: 813-4.
Wilhelm D, Palmer S, Koopman P. Sex determination and gonadal development in mammals. Physiol Rev
2007; 87: 1-28.
Mullen RJ, Whitten WK. Relationship of genotype and degree of chimerism in coat color to sex ratios and gametogenesis in chimeric mice. J Exp Zool
1971; 178: 165-76.
Singh L, Matsukuma S, Jones KW. Testis development in a mouse with 10% of XY cells. Dev Biol
1987; 122: 287-90.
Lavery R, Lardenois A, Ranc-Jianmotamedi F, Pauper E, Gregoire EP, et al.
XY So×9 embryonic loss-of-function mouse mutants show complete sex reversal and produce partially fertile XY oocytes. Dev Biol
2011; 354: 111-22.
Lovell-Badge R, Robertson E. XY female mice resulting from a heritable mutation in the primary testis-determining gene, Tdy. Development
1990; 109: 635-46.
Mahadevaiah SK, Lovell-Badge R, Burgoyne PS. Tdy-negative XY, XXY and XYY female mice: breeding data and synaptonemal complex analysis. J Reprod Fertil
1993; 97: 151-60.
Capel B, Rasberry C, Dyson J, Bishop CE, Simpson E, et al.
Deletion of Y chromosome sequences located outside the testis determining region can cause XY female sex reversal. Nat Genet
1993; 5: 301-7.
Vernet N, Szot M, Mahadevaiah SK, Ellis PJ, Decarpentrie F, et al.
The expression of Y-linked Zfy2 in XY mouse oocytes leads to frequent meiosis 2 defects, a high incidence of subsequent early cleavage stage arrest and infertility. Development
2014; 141: 855-66.
Eicher EM, Washburn LL, Whitney JB 3 rd
, Morrow KE. Mus poschiavinus Y chromosome in the C57BL/6J murine genome causes sex reversal. Science
1982; 217: 535-7.
Lee CH, Taketo T. Normal onset, but prolonged expression, of Sry gene in the B6.YDOM sex-reversed mouse gonad. Dev Biol
1994; 165: 442-52.
Taketo T, Lee CH, Zhang J, Li Y, Lee CY, et al
. Expression of SRY proteins in both normal and sex-reversed XY fetal mouse gonads. Dev Dyn
2005; 233: 612-22.
Taketo-Hosotani T, Nishioka Y, Nagamine CM, Villalpando I, Merchant-Larios H. Development and fertility of ovaries in the B6.YDOM sex-reversed female mouse. Development
1989; 107: 95-105.
Alton M, Lau MP, Villemure M, Taketo T. The behavior of the X- and Y-chromosomes in the oocyte during meiotic prophase in the B6.Y (TIR) sex-reversed mouse ovary. Reproduction
2008; 135: 241-52.
Amleh A, Ledee N, Saeed J, Taketo T. Competence of oocytes from the B6.YDOM sex-reversed female mouse for maturation, fertilization, and embryonic development in vitro
. Dev Biol
1996; 178: 263-75.
Amleh A, Smith L, Chen H, Taketo T. Both nuclear and cytoplasmic components are defective in oocytes of the B6.Y (TIR) sex-reversed female mouse. Dev Biol
2000; 219: 277-86.
Villemure M, Chen HY, Kurokawa M, Fissore RA, Taketo T. The presence of X- and Y-chromosomes in oocytes leads to impairment in the progression of the second meiotic division. Dev Biol
2007; 301: 1-13.
Obata Y, Villemure M, Kono T, Taketo T. Transmission of Y chromosomes from XY female mice was made possible by the replacement of cytoplasm during oocyte maturation. Proc Natl Acad Sci U S A
2008; 105: 13918-23.
Xu B, Obata Y, Cao F, Taketo T. The presence of the Y-chromosome, not the absence of the second X-chromosome, alters the mRNA levels stored in the fully grown XY mouse oocyte. PLoS One
2012; 7: e40481.
Burgoyne PS, Mahadevaiah SK, Turner JM. The consequences of asynapsis for mammalian meiosis. Nat Rev Genet
2009; 10: 207-16.
Morelli MA, Cohen PE. Not all germ cells are created equal: aspects of sexual dimorphism in mammalian meiosis. Reproduction
2005; 130: 761-81.
Roeder GS, Bailis JM. The pachytene checkpoint. Trends Genet
2000; 16: 395-403.
Ashley T, Westphal C, Plug-de Maggio A, de Rooij DG. The mammalian mid-pachytene checkpoint: meiotic arrest in spermatocytes with a mutation in Atm alone or in combination with a Trp53 (p53) or Cdkn1a (p21/cip1) mutation. Cytogenet Genome Res
2004; 107: 256-62.
de Rooij DG, de Boer P. Specific arrests of spermatogenesis in genetically modified and mutant mice. Cytogenet Genome Res
2003; 103: 267-76.
Burgoyne PS, Mahadevaiah SK, Sutcliffe MJ, Palmer SJ. Fertility in mice requires X-Y pairing and a Y-chromosomal "spermiogenesis" gene mapping to the long arm. Cell
1992; 71: 391-8.
Baarends WM, Wassenaar E, van der Laan R, Hoogerbrugge J, Sleddens-Linkels E, et al.
Silencing of unpaired chromatin and histone H2A ubiquitination in mammalian meiosis. Mol Cell Biol
2005; 25: 1041-53.
Mahadevaiah SK, Bourc'his D, de Rooij DG, Bestor TH, Turner JM, et al
. Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation. J Cell Biol
2008; 182: 263-76.
Mahadevaiah SK, Turner JM, Baudat F, Rogakou EP, de Boer P, et al.
Recombinational DNA double-strand breaks in mice precede synapsis. Nat Genet
2001; 27: 271-6.
Royo H, Polikiewicz G, Mahadevaiah SK, Prosser H, Mitchell M, et al.
Evidence that meiotic sex chromosome inactivation is essential for male fertility. Curr Biol
2010; 20: 2117-23.
Turner JM, Aprelikova O, Xu X, Wang R, Kim S, et al.
BRCA1, histone H2AX phosphorylation, and male meiotic sex chromosome inactivation. Curr Biol
2004; 14: 2135-42.
Ichijima Y, Ichijima M, Lou Z, Nussenzweig A, Camerini-Otero RD, et al.
MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells. Genes Dev
2011; 25: 959-71.
Turner JM, Mahadevaiah SK, Fernandez-Capetillo O, Nussenzweig A, Xu X, et al.
Silencing of unsynapsed meiotic chromosomes in the mouse. Nat Genet
2005; 37: 41-7.
Homolka D, Jansa P, Forejt J. Genetically enhanced asynapsis of autosomal chromatin promotes transcriptional dysregulation and meiotic failure. Chromosoma
2012; 121: 91-104.
Sciurano R, Rahn M, Rey-Valzacchi G, Solari AJ. The asynaptic chromatin in spermatocytes of translocation carriers contains the histone variant gamma-H2AX and associates with the XY body. Hum Reprod
2007; 22: 142-50.
Solari AJ. The spatial relationship of the X and Y chromosomes during meiotic prophase in mouse spermatocytes. Chromosoma
1970; 29: 217-36.
McClellan KA, Gosden R, Taketo T. Continuous loss of oocytes throughout meiotic prophase in the normal mouse ovary. Dev Biol
2003; 258: 334-48.
Ene AC, Park S, Edelmann W, Taketo T. Caspase 9 is constitutively activated in mouse oocytes and plays a key role in oocyte elimination during meiotic prophase progression. Dev Biol
2013; 377: 213-23.
Speed RM. Oocyte development in XO foetuses of man and mouse: the possible role of heterologous X-chromosome pairing in germ cell survival. Chromosoma
1986; 94: 115-24.
Turner JM, Mahadevaiah SK, Benavente R, Offenberg HH, Heyting C, et al
. Analysis of male meiotic "sex body" proteins during XY female meiosis provides new insights into their functions. Chromosoma
2000; 109: 426-32.
Taketo T, Naumova AK. Oocyte heterogeneity with respect to the meiotic silencing of unsynapsed X chromosomes in the XY female mouse. Chromosoma
2013; 122: 337-49.
Bianchi NO. Akodon sex reversed females: the never ending story. Cytogenet Genome Res
2002; 96: 60-5.
Hoekstra HE, Hoekstra JM. An unusual sex-determination system in South American field mice (Genus Akodon): the role of mutation, selection, and meiotic drive in maintaining XY females. Evolution
2001; 55: 190-7.
Paul-Prasanth B, Bhandari RK, Kobayashi T, Horiguchi R, Kobayashi Y, et al.
Estrogen oversees the maintenance of the female genetic program in terminally differentiated gonochorists. Sci Rep
2013; 3: 2862.
[Figure 1], [Figure 2]