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Biology of Reproduction 67, 1646-1652 (2002)
© 2002 Society for the Study of Reproduction, Inc.

Regular Article

Sex-Specific Gene Expression During Meiotic Prophase I: Xlr (X Linked, Lymphocyte Regulated), Not Its Male Homologue Xmr (Xlr Related, Meiosis Regulated), Is Expressed in Mouse Oocytes

Denise Escalier1,a, Laure Eloyb, and Henri-Jean Garchonb

a Laboratoire de Cytologie et Histologie, EA1533, 45, Rue des Saints Pères, 75270 Paris Cedex 06, France b INSERM U25, Hôpital Necker, 161, rue de Sèvres, 75743 Paris Cedex 15, France


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The Xmr (Xlr related, meiosis regulated) gene product is abundantly expressed in primary spermatocytes and is notably associated with nonrecombining segments of sex chromosomes in the XY body. Here we determined whether Xmr was expressed in meiotic oocytes. This was done by reverse transcription-polymerase chain reaction and cDNA sequencing, Western blot analysis, and immunocytochemistry. Unexpectedly, no Xmr message was detected in mouse fetal oocytes. Instead, Xlr (X linked, lymphocyte regulated), a closely related gene expressed in fetal thymus cells at the time of antigen-receptor gene rearrangement, was expressed in oocytes throughout meiotic prophase I. These findings indicate a sex-specific expression of two closely related members of the Xlr gene family during meiotic prophase I. The XLR protein may provide a useful marker for studies on chromatin condensation or DNA recombination in oocytes. In addition, because of the localization of the Xlr sequence family on the mouse X chromosome, the human equivalent of Xlr is a candidate gene for premature ovarian failure.

gametogenesis, meiosis, oocyte development, ovary, spermatogenesis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The molecular mechanisms underlying mammalian oogenesis are still ill understood. Their study will be greatly aided by the knowledge of the genes expressed at the various steps of this unique developmental process. However, whereas detailed studies of the transcriptome of mammalian spermatocytes have been undertaken, an exhaustive description of the genes expressed during oocyte development has not been proposed yet because of obvious technical difficulties. Identification of genes and loci involved in mammalian oogenesis thus had to rely on alternative approaches. In mice, targeting of candidate genes, which often play a role in DNA recombination or repair, has provided most valuable information [1–3]. In humans, cytogenetic analysis of X chromosome abnormalities associated with premature ovarian failure (POF) pointed to a role of X-linked loci, many of which remain to be identified at the molecular level [4–8].

Another means of identifying genes associated with female meiosis relies on the examination of genes known to be expressed during male meiosis. In this regard, the murine Xmr gene product is a good candidate to investigate an expression in oocytes. It is a protein of 212 amino acids, with a molecular weight of approximately 30 000, that is specifically expressed in primary spermatocytes throughout prophase I of meiosis [9]. It is strongly associated with the asynapsed segments of the XY body [10]. This subnuclear structure, also called sex vesicle, is formed transiently and is thought to play an essential role in maintenance of genetic integrity of sex chromosomes by preventing their recombination during male meiosis except at the level of the pseudoautosomal region [11].

The Xmr gene was identified as a result of its close sequence similarity with the Xlr gene (X linked, lymphocyte regulated). The latter gene encodes a 208-amino acid nuclear protein that is expressed in the somatic lineage specifically and at a high level in fetal thymus cells, at the pre-T cell stage, in concert with T-cell receptor locus rearrangement. Moreover, the XLR protein colocalizes with SATB1 [12], a protein component of the nuclear matrix that binds particular AT-rich sequences and appears to regulate the expression of many genes [13–15].

The genes that encode the XLR and XMR proteins belong to a large family of closely homologous sequences, called Xlr, as this was its first discovered member [16]. This family has an estimated number of 50–75 copies per haploid genome and includes a majority of pseudogenes [17]. Most Xlr sequences appear to be distributed on the proximal part of the X chromosome in two distinct clusters that have been designated Xlr1 and Xlr2 on the basis of their cytogenetic location. Presently, it is not known where the genes that encode XLR and XMR map relative to the Xlr1 and Xlr2 clusters. Subsequently, three additional groups of Xlr sequences, Xlr3, Xlr4, and Xlr5, were identified [18, 19]. They are distantly related to each other and to Xlr1/Xlr2. Their transcripts contain open reading frames that display 20–39% amino acid identity with XLR and XMR. The corresponding protein products, however, have not been characterized.

The function of XMR and XLR is unknown. Both proteins bear significant sequence similarity with other meiosis-specific proteins, including mammalian SCP3/COR1 [20, 21] and MER2 in Saccharamyces cerevisiae [22]. These similarities, together with the highly specific pattern of developmental expression, led us to propose that XLR/XMR could play a role in chromatin condensation or DNA recombination in their respective cell lineage [10]. In the present study, we investigated whether a member of the Xlr family was expressed in female oocytes.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Mice and Fetuses

C57BL/6J mice used in this study were housed under specific pathogen-free conditions in our animal facility, in keeping with the European Union legislation on animal care. Single females (3–5 mo of age) were mated with males. They were checked every morning for the presence of vaginal plug, as evidence of copulation. The day of plug was counted as Day 0 of pregnancy. Ovaries from adult females and from fetuses and newborns from Day 14 of gestation to Day 5 postpartum were considered for the study. Pregnant females were anesthetized and killed by cervical dislocation. Their abdomen and uterus were opened and the fetuses removed. Each fetus had the gonads removed under a dissecting microscope. Newborn mice were anesthetized and killed by decapitation. Their ovaries were immediately dissected out. Isolated testicular germ cells were obtained as previously described [9].

Complementary DNA Amplification and Determination of Nucleotide Sequence

Total RNA was extracted from Day 18 fetal ovaries with the guanidinium thiocyanate-acid phenol procedure and retrotranscribed from the polyA tail using Superscript RNAseH-minus Moloney-MuLV reverse transcriptase (Life Technologies, Cergy Pontoise, France). An aliquot of cDNA was polymerase chain reaction (PCR)-amplified with C1 (5'-CCTGAAGAAGTAGTTGGAGATACA-3') and COD2R (5'-ACTAGAAGAGTACTTCAGAGTATG-3') oligonucleotide primers that anneal to sequences identical in Xlr and Xmr. Reactions were conducted in a 100-µl mix containing 1 µmole/L of each primer, 200 µmole/L of each dNTP, 20 mM Tris-HCl pH 8.3, 50 mM KCl, 1.5 mmole/L MgCl2, and 10 U of Taq DNA polymerase (Life Technologies). Cycling conditions were 94°C for 1 min, 62°C for 1 min, and 72°C for 1 min for 30–45 cycles. PCR products were migrated on a 1% agarose gel, stained with ethidium bromide (1 µg/ml), and visualized by UV transillumination. Pictures were taken, scanned, and analyzed with the NIH Image software v1.61.

The sequence of the full-length cDNA was obtained after amplification and cloning of the cDNA ends with the 5'RACE (rapid amplification of cDNA ends) System (Life Technologies). Briefly, total RNA was retrotranscribed using SuperScript and a gene-specific antisense oligonucleotide, COD2R. RNA was then degraded and the cDNA was purified using GlassMAX spin cartridges. Purified cDNA was dC-tailed with terminal-d-transferase (TdT) and 0.2 mM dCTP in a 25-µl volume for 10 min at 37°C. After heat inactivation of TdT, the tailed cDNA was PCR-amplified with the 5'RACE abridged anchor primer (5'-GGCCACGCGTCGACTAGTACGGGIIGGGIIGGGIIG-3') and COD2R. Additional rounds of amplification were performed with the universal amplification primer provided by the manufacturer and a nested cognate primer (xlr5', 5'-CATCATCACGAGTTACTGGA-3'). PCR products were cloned directly in a T-vector and transfected in DH5{alpha} Escherichia coli. Recombinant plasmid was prepared from transformed bacteria and subjected to dideoxy sequencing using the ABI Prism Dye Terminator cycle sequencing kit (Applied Biosystems, Foster City, CA) with the SP6 and T7 primers. The sequencing products were migrated on an ABI-373XL automated DNA Sequencer (Applied Biosystems).

Immunoblot Analysis

Ovaries and male germ cells were harvested as above and were lysed directly in 1x reducing sample buffer. Electrophoresis and Western blot analysis were then performed as previously described using a murine monoclonal anti-XLR antibody or an isotype-matched control immunoglobulin [9]. Biotinylated antibodies against mouse IgG (from sheep) and streptavidin-horseradish conjugated to peroxidase were purchased from Amersham (Amersham Pharmacia Biotech UK, Buckinghamshire, UK).

Immunohistochemistry and Immunocytochemistry

Ovaries from adult female, fetus, and newborn mice were gently pressed between microscopy fat off slides [23]. Other ovaries were frozen and sectioned. Both germ cell preparations and sections were immediately fixed for 15 min with 1% formaldehyde in PBS containing 3% sucrose. Germ cell preparations were subsequently treated for 5 min with 0.1% Triton X-100 in PBS. Alternatively, ovaries were fixed before freezing with 4% paraformaldehyde in PBS for 3 h, washed, and incubated in PBS containing 12, 15, and 18% (w/v) sucrose successively.

Germ cells preparations and ovary sections were then incubated for 1 h in 5% non fat milk in PBS. They were then incubated with an anti-XLR antibody or with a control myeloma protein, MOPC21, of the same isotype, IgG1{kappa}. Peroxidase labeling was performed following the three-step technique using the biotin-streptavidin system and amino-ethyl-carbazole as the chromogen. Cells were then counterstained, or not, with Harris hematoxylin and mounted in aqueous medium (Glycergel, Dakopatts, Glostrup, Denmark).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Xlr Transcripts in Mouse Fetal Ovaries

Mouse fetal ovaries were harvested at Day 18 of gestation. At this stage, oocytes are in prophase I of meiosis. Total RNA was extracted and retrotranscribed. The cDNA was then PCR amplified with oligonucleotide primers C1 and COD2R, which anneal to sequences identical between Xlr and Xmr, to minimize a potential bias of amplification (Fig. 1A). With these primers, amplification of the Xmr message yields a product of 298 base pairs (bp) and the Xlr message a product of 501 bp. Both products therefore can be easily distinguished by their size and quantitated following agarose gel electrophoresis and ethidium bromide staining. As shown on Figure 1B, an Xlr-like PCR product was amplified from fetal oocytes, whereas Xmr was barely detected after 45 PCR cycles. Conversely, in adult testes, Xmr was abundantly expressed, whereas Xlr was not amplified.



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  		FIG. 1. RT-PCR detection of an Xlr message in Day 18 fetal ovary. A) Diagram showing the approximate location of the primers used for RT-PCR on the cDNA sequence of Xlr and of Xmr. The hatched rectangles identify the regions of close sequence similarity between Xmr and Xlr. The primers themselves anneal to sequences identical between Xlr and Xmr. They amplify a fragment of 501 bp from Xlr and of 298 bp from Xmr. B) Semiquantitative RT-PCR of Xlr (closed symbols) and Xmr (open symbols) sequences in Day 18 fetal ovary (circles) and in adult testis (triangles). PCR fragments were generated from reverse-transcribed total RNA using the primers shown in A. They were quantitated by densitometry after gel electrophoresis and ethidium bromide staining using the NIH Image analysis software. The data are expressed as arbitrary units measured after different numbers of PCR cycles

The nucleotide sequence of the Xlr-like PCR product was verified by direct sequencing, and the full-length cDNA sequence was completed with the RACE protocol. It was identical to that previously obtained for the Xlr message in lymphoid cell lines and in fetal thymocytes.

Expression of an XLR-Related Protein in Fetal Ovaries

Western blot analysis of Day 17 fetal ovary extracts with an anti-XLR monoclonal antibody showed the presence of a molecular species of Mr 30 000 (Fig. 2, lane 3). No expression of XLR was detected in adult ovaries and in fetal testes (Fig. 2, lanes 4 and 5). This lack of XLR expression in adult ovary was consistent with the absence of Xlr-related mRNA that was previously reported [9].



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  		FIG. 2. Immunoblot detection of an Xlr gene product in fetal ovary. Recombinant XLR protein (lane 1) and extracts prepared from Day 17 fetal thymuses (lane 2), from Day 17 fetal ovaries (lane 3), from adult ovaries (lane 4), and from Day 17 fetal testes (lane 5) were migrated on a denaturing 12% polyacrylamide gel electrophoresis, blotted onto nylon membrane, and probed with an anti-XLR monoclonal antibody (A) or with a control myeloma protein of the same isotype IgG1{kappa}, MOPC21 (B).

Stage-Specific Nuclear Localization of the Gene Product During Meiotic Prophase

As described in the C57BL/6 strain [24], oocytes enter meiosis at the leptotene stage at Day 14 of fetal life. They proceed through the successive stages of prophase I until diplotene, around birth. At this stage, they become dictyate. Meiosis is arrested and resumes after puberty. However, there is variability in this pattern [25–27], likely because progression of oocytes through prophase I is not synchronous [28].

Immunolabeling with the anti-XLR monoclonal antibody was first performed on ovary cryosections from Day 17 fetuses until Day 5 after birth. As already noted, synchronous germ cells were grouped in clusters [27]. At Days 17 and 18, the whole nucleus of oocytes was stained for XLR (Fig. 3, A and B). In contrast, the somatic cells were not immunoreactive. The labeling pattern of ovaries fixed before freezing was homogeneous (Fig. 3A). This was not the case in sections from ovaries that were directly frozen, then sectioned and fixed (Fig. 3B). In this case, areas of the nucleus looking like strands appeared more intensely stained (compare Fig. 3, A and B). Direct sectioning of freshly frozen ovaries followed by fixation seemed to provide a sharper image, reflecting the shape and the fine structure of the nuclei, compared with frozen sections of fixed ovaries. At birth and on subsequent days, expression of XLR was turned off (Fig. 3C). In agreement with a previous report [28], oocytes at different stages of prophase I were observed in fetal ovaries and this asynchrony persisted up to Day 2 after birth (data not shown). Ovary sections from fetuses at Day 18 and incubated with control isotype-matched immunoglobulin, MOPC21, were unstained (Fig. 3D).



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  		FIG. 3. Frozen section of ovaries harvested from Day 17 (A) and Day 18 (B, D) embryos or at Day 2 after birth (C), immunolabeled with an anti-XLR monoclonal antibody (A–C) or with a control IgG1{kappa} myeloma protein, MOPC21 (D). A, C) Ovary was fixed before freezing and sectioning. B, D) Ovaries were directly frozen and then sectioned and fixed. Arrows point to XLR-labeled nuclei of prophase I oocytes (A and B) or to unlabeled dictyate oocytes that are surrounded by follicular cells (C). Bars = 10 µm

Immunodetection of XLR with the anti-XLR monoclonal antibody was then performed on fresh oocytes from ovaries that were gently pressed between fat-off microscopy slides [23]. Ovary prints were not possible due to their small size and their jellied consistency. We assumed that germ cells enter meiosis at Day 14 of fetal life (E14) and that the meiotically arrested oocytes become surrounded by somatic cells by Day 2 after birth, forming primordial follicles. On this basis, we investigated daily time points between E14 and Day 5 after birth. Stages of meiosis were identified according to cytological characteristics of oocytes as described [24, 25]. The characteristics of nucleoli at different stages were defined as previously [29].

At leptotene, chromatin begins to shorten and condense. The nucleus contains a mass of fine threads of chromatin. Two or three nucleoli are often visible. XLR was detected in the whole nucleus except in the nucleoli (Fig. 4A). At zygotene, chromosomal threads thicken (corresponding to the beginning of chromosomal pairing) and nucleoli are very faint. At this stage, the XLR labeling pattern was slightly stronger (Fig. 4B). Shortening and thickening of paired chromosomes are maximal at pachytene (Fig. 4C). Throughout early and midpachytene, nucleoli are rarely visible. At this stage, the XLR concentrated on the condensed chromosomes (Fig. 4C). During late pachytene, the chromosomes take a lampbrush appearance (Fig. 4D). XLR was displaced, leading to a heterogeneous aspect with a staining concentrated in localized regions, including domains looking like nucleoli, while other nuclear domains had lost immunoreactivity (Fig. 4D). Diplotene nuclei retain the lampbrush configuration, and the chromosomes become longer and thinner and the nuclei are extensively deformed. Two or three prominent nucleoli are again visible (Fig. 4E). At this stage, the XLR amount decreased except in regions looking like nucleoli (Fig. 4E). At dictyotene, the chromosomes are decondensed (Fig. 4F); the nucleoli remain quite prominent and seem to merge into one large nucleolus located at the center of the nucleus. By this time, the dictyate oocyte becomes surrounded by a complete layer of follicular cells. At this stage, XLR had disappeared. As for sections from frozen ovaries (Fig. 3D), fresh oocytes from ovaries pressed on slides and incubated with the control immunoglobulin MOPC21 were unlabeled (Fig. 4G). Likewise, XLR was not detected on ovary prints from adult (6-wk-old) females (data not shown).



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  		FIG. 4. Expression of XLR during meiotic prophase I. Fresh oocytes were prepared from ovaries of fetuses at different days of their development to capture the successive stages of prophase I, including leptotene (A), zygotene (B), midpachytene (C), late pachytene (D), diplotene (E), and dictyate (F). Arrowheads in A and F point to nucleoli. Stars in D and E point to nuclear structures possibly related to nucleoli. Arrows in F point to the layer of follicular cells surrounding dictyate oocytes. Fresh oocytes were labeled with an anti-XLR monoclonal antibody (A–F) or with a control IgG1, MOPC21 (G). Bars = 10 µm

Taken together, our data showed that the oocyte nuclei were stained by anti-XLR antibody throughout prophase I of meiosis. The staining was strongest at pachytene, faded at diplotene, and disappeared in dictyate oocytes.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In humans, the prevalence of POF is 2–3% in women [30–32]. POFs, however, are heterogeneous and their etiology is unknown in 52.5% of cases [33–35]. A number of these idiopathic POFs are likely to result from improper prenatal oocyte development, as suggested by the extensive observation of oocytes during the practice of intracytoplasmic sperm injection (ICSI) [1]. A family history is also reported in 12.7–37.5% of the cases, which suggests that they are caused by a genetic alteration [30–32, 36, 37]. Understanding the molecular basis of these defects is therefore of considerable research and clinical interest. However, it is also a considerable task because of the difficulty of obtaining prefollicular oocytes in women [38, 39]. Valuable information can be gathered from the study of animal models [36]. This approach is also supported by the finding of a high percentage of homologous genes expressed in ovaries in humans and in mice [37].

In the present study, we characterized an expression of a member of the Xlr family in mouse fetal oocytes at both the mRNA and the protein level. At the message level, a unique sequence was detected. It was identical to Xlr, which is expressed in lymphoid cells [40] and in fetal thymocytes [12]. The fine expression of the protein product was then studied by immunocytochemistry. The stability of antigenic epitopes of XLR proteins following treatments is unpredictable and had necessitated resorting to thymic prints in a previous study [12]. Therefore, to increase reliability of the labeling, we employed two protocols for preparing samples prior to their labeling. One protocol used sections of frozen ovaries, whereas the other used ovary cells deposited on slides. Because XLR/XMR is likely to be associated with matrix-associated regions of the chromatin [12] and with chromatin loops in spermatocytes [10], an association with the synaptonemal complexes might be masked. In this case, meiotic cell spreads would be useful to detect it. However, this technique induces important changes in the nuclear matrix and in chromosomal loops and must be employed with caution. In this respect, the ataxia-telangectasia mutated (Atm) gene product was conserved only on the axis of synapsed chromosomes following spreading [41], while tissue sections revealed that ATM was present in the whole nuclei [42, 43].

We found that XLR was expressed throughout prophase I of female meiosis. Likewise, XMR was expressed during the entire prophase I in male germ cells. The fact that two closely related proteins are expressed in the germline in a sex-specific manner may well provide the first example of molecular differentiation during meiotic prophase. It could be related to differences in nuclear events occurring during meiosis in male and female. In the female, the inactive X chromosome is reactivated shortly before the cells enter meiosis [44] and, throughout the prophase, chromatin of both X chromosomes takes on a conformation that is indistinguishable from that of the autosomes. The X chromosomes pair and participate in recombination over their entire length [45]. In contrast, in spermatocytes, the nuclei are the site of male-specific chromosomal events, the most characteristic of which is the segregation of sex chromosomes apart from the autosomes in a specific domain of the nucleus. The formation of the XY body is thought to play an essential role in inactivation and in restriction of XY pairing to the pseudoautosomal region [11].

Although a differential expression of Scp3 and Pms2 in male and female germ cells has not been directly demonstrated, the inactivation of these genes cause infertility in males but not in females, suggesting additional examples of sex-restricted meiosis-specific genes [46, 47]. However, it is worth noting that although their follicular development was not affected, the fertility of Scp3-deficient females was reduced as a consequence of chromosomal segregation errors leading to oocyte aneuploidy [48]. In contrast, other meiosis-specific genes, including Mlh1, Msh4, Msh5, and Dmc1, alter the development of the germline in both sexes when inactivated [49–53].

To further characterize the function of Xlr in oocyte development, inactivation of the gene would be helpful to achieve. However, because of the multigenic nature of the Xlr family and the close sequence similarity of the many members of this large family, inactivation by homologous recombination cannot be considered for the time being. The phenotype caused by an impaired expression of Xlr would be certainly difficult to anticipate. Inactivation of a gene with a pivotal role in the recombination machinery is often associated with germ cell apoptosis resulting from meiotic checkpoint controls [54]. However, especially in females, phenotypes are eventually very diverse [51]. In Dmc1 null mice, an oocyte loss occurs in neonates, with retention of a rudimentary ovary in adulthood [52, 53]. In Msh5 null mice, loss of oocytes begins in embryonic life and is almost complete in newborns, when the ovary begins to degenerate such that, in the adult, it is entirely absent or consists of a few large cysts [51]. In Mlh1 null female mice, ovaries had very few follicles, ovulation occurred infrequently [49], and eggs never completed meiosis II [50]. However, oocytes arrested in meiotic prophase I could be found in a fully developed follicle and be normally released at ovulation [50].

In humans, much less is known about arrests of oocytes at stages of meiotic recombination. Strategies to characterize the etiology of female infertility should rely, in particular, on the search for mutation(s) in genes expressed during meiotic recombination. Identification of these genes, among which the human equivalent Xlr is a candidate [55], should be the first step toward this goal. Interestingly, Xlr sequences have been localized in regions of the murine X chromosome for which human homologous syntenies are located either on the short arm of the X chromosome, between the centromere and Xp21, or on its long arm, between Xq26 and the telomere [56]. Human POF genes also have been mapped on the short arm (Xp11.2–q22.1) and on the long arm (Xq13–q26) of the X chromosome [57]. Therefore, one could propose that the human equivalent of Xlr, which remains to be identified, is a candidate for POF in women.


   FOOTNOTES
 
1 Correspondence: Denise Escalier, Laboratoire de Embryology, Université Paris 5, 45, Rue des Saints Pères, 75270 Paris Cedex 06, France.FAX: 33 1 42 86 20 84; denise.escalier{at}biomedicale.univ-paris5.fr Back

Received: 27 April 2002.

First decision: 22 May 2002.

Accepted: 20 June 2002.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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