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Ovary |
a Children's Hospital and Program for Developmental and Reproductive Biology, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland
b The Folkhälsan Institute of Genetics and Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland
c Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNOTE ADDED IN PROOFREFERENCES |
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developmental biology, early development, female reproductive tract, gene regulation, ovary
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNOTE ADDED IN PROOFREFERENCES |
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The transcription factor GATA-4 has been implicated in the development and function of the gonads. GATA-4 belongs to a family of zinc finger transcription factors termed the GATA-binding proteins, which bind to a consensus GATA motif, (A/T)GATA(A/G) in the promoters and enhancers of their target genes (for review, see [6, 7]). GATA-4, GATA-5, and GATA-6 form a subfamily within the GATA proteins, and a number of tissues, including heart and tissues of endodermal origin, express them [7]. Among other factors, GATA-4 is critical in the developing heart; mice homozygously deficient in Gata4 die 7.0–10.5 days postcoitum (dpc) as a result of failure in the lateral to ventral folding of the embryo [8, 9].
Of the six known GATA factors, GATA-1, GATA-2, GATA-4, and GATA-6 are apparent in the gonads. GATA-1 is present in the postnatal mouse Sertoli cells [10], whereas GATA-2 is present in the germ cells of early fetal mouse ovaries [11]. In mouse and human postnatal ovaries, granulosa cells from primary follicles onward express GATA-4, and GATA-6 is expressed in larger follicles and in luteal glands [12, 13]. Both factors are also detectable in the ovarian theca and interstitial cells. In the mouse and human testis, Sertoli and Leydig cells express GATA-4 [14, 15]. The gonadotropins FSH and hCG stimulate GATA-4 expression in mouse granulosa, Sertoli, and Leydig tumor cell lines [12, 14] and GATA-6 in human granulosa-luteal cells [13]. The role of GATA factors in gonadogenesis has been further elucidated by identifying their downstream target genes, which include MIS (Müllerian-inhibiting substance) [16–18], inhibin 
and ß-B subunits [14, 19], SF-1 (steroidogenic factor 1) [20], StAR (steroidogenic acute regulatory protein) [20, 21], and aromatase [20, 22]. Synergistic action of GATA-4 and SF-1 is essential for full activation of the MIS, inhibin-, and aromatase genes in vitro [17, 18, 20].
The specificity of gene regulation by GATA factors is achieved in part by cofactors acting in concert with them. Two related factors, FOG (friend of GATA)-1 and FOG-2, interact with the GATA factors by binding to their N-terminal zinc finger [23–26]. In vitro experiments revealed that FOG-1 and FOG-2 can either activate or repress the action of GATA-1 or GATA-4, or both. Accordingly, FOG-2 represses the transactivation of various GATA targets in the murine heart [25–27]. The function of FOG-2 is, however, target gene or cell specific. Accordingly, FOG-2 in heterologous cells increases and in cardiac cells represses the stimulatory effect of GATA-4 on some of its target genes, e.g., on the -Myosin Heavy Chain [26]. FOG-2 is also significant for proper heart development; mice deficient in Fog2 suffer from heart failure and die in utero 12.5–15.5 dpc [28, 29]. The critical interplay of FOG-2 and GATA-4 has been further verified by impairing their physical interaction, resulting in death at 13.5 dpc [30]. The possible gonadal phenotype of these animals is unknown.
GATA-4 expression is thought to be downregulated in the fetal mouse ovary shortly after ovarian differentiation [12, 16], whereas it is maintained in the fetal testis, accompanying MIS expression [14, 16]. In contrast to the findings in female mice, GATA-4 is evident in the human and porcine ovary during the entire fetal period [31, 32]. FOG-2 is expressed in the E11.5 mouse urogenital ridge and in the E16.5 gonad, but the possible sexual dimorphism in its appearance remains unclear [24, 25]. FOG-2 diminishes the transactivation of MIS promoter by GATA-4 in cultured postnatal rat Sertoli cells endogenously expressing FOG-2 [33]. Likewise, postnatal mouse testis expresses FOG-2, together with FOG-1 [23–26]; we have recently localized these proteins to the Sertoli cells in particular [34]. In the mouse ovary, however, FOG-1 expression has not been demonstrated (unpublished results). FOG-2 is apparent in human ovarian granulosa-luteal cell cultures and in granulosa and theca cell tumor specimens [13], but its possible role in mouse ovary is unexplored.
We surveyed the expression of FOG-2 in fetal mouse gonads and in postnatal ovary in detail and compared it with that of GATA-4. The results suggest that FOG-2 and GATA-4 probably play distinctive roles during ovarian development from fetal to postnatal life. Moreover, transactivation studies strongly support a role for the cooperation of GATA-4 and FOG-2 in the regulation of MIS expression.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNOTE ADDED IN PROOFREFERENCES |
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CBA or NMRI mice were mated, and noon of the day the vaginal plug appeared was designated as Embryonic Day 0.5 (E0.5). Gonads were dissected in Dulbecco modified Eagle medium from animals killed at E12, E13, E15, and E17 and at Postnatal Days 1, 7, 14, 25, and 60; E10 embryos were used entirely. The samples were snap frozen or fixed in 4% paraformaldehyde (PFA), dehydrated, and embedded in paraffin. Sex of the E10 and E12 embryos was determined by polymerase chain reaction (PCR) analysis for Sry gene of genomic DNA extracted from the head of the animal by a commercial kit (QIAamp 51304; Qiagen, Hilden, Germany). Primers for this analysis were 5'-AAGCGCCCCATGAATGCATT-3' and 5'-ATATTTATAGTCGGAGTAGC-3', and conditions for PCR were as described previously [35]. The expected 218-base pair (bp) product [36] was size-fractioned in a 1% agarose gel. All the animal studies were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
Northern Blot Analysis
Total cellular RNA was extracted by the guanidine isothiocyanate-cesium chloride method or by a commercial kit (RNeasy 74104; Qiagen), quantified by absorbance at 260 nm, and size-fractionated in a 1.5% agarose-formaldehyde gel (14 µg/lane) [31]. As templates for cDNA probes, a fragment of mouse GATA-4 cDNA [37] and a BamH1-Kpn1 fragment of mouse FOG-2 cDNA (base pairs 1–800) subcloned from the pCS2+-FOG-2 full-length expression vector [24] were used; a probe for 18S rRNA (7328; Ambion, Austin, TX) was employed as a loading control. Preparation of the 32P-labeled radioactive probes and hybridizations were carried out as described previously [31].
In Situ Hybridization
Serial sections of PFA-fixed gonads embedded in paraffin were subjected to in situ hybridization, using the same templates for GATA-4 and FOG-2 riboprobes as used for Northern blots. Tissue sections were incubated o/n with 106 cpm of 33P-labeled riboprobe (1000–3000 Ci/mmol; Amersham, Arlington Heights, IL) in a total volume of 80 µl following a protocol previously described [12]. A corresponding sense probe was used as a negative control for the antisense probes.
Immunohistochemistry
Paraffin-embedded sections were deparaffinized, hydrated, and treated with 10 mmol/L citric acid in a microwave oven for 10–20 min to improve antibody penetration. Endogenous peroxidase activity was blocked with 3% hydrogen peroxidase, and nonspecific binding was prevented by using 1.5% normal serum. As primary antibody, we used polyclonal goat anti-mouse GATA-4 IgG (sc-1237; Santa Cruz Biotechnology, Santa Cruz, CA), rabbit anti-mouse GATA-6 IgG (sc-9055; Santa Cruz Biotechnology), rabbit anti-mouse FOG-2 IgG (sc-10744; Santa Cruz Biotechnology), and goat anti-mouse MIS IgG (sc-6886; Santa Cruz Biotechnology). The sections were exposed to the antibody at dilutions of 1:200 to 1:500 for 1 h at 37°C or o/n at 4°C (FOG-2). An avidin-biotin immunoperoxidase system (Vectastain Elite ABC Kit; Vector Laboratories, Burlingame, CA) and diaminobenzidine (DAB; Sigma Chemicals, St. Louis, MO) was used to visualize the bound antibody; sections were counterstained with 100% hematoxylin. The primary antibody was replaced with preimmune serum or plain PBS as a negative control. Double immunohistochemistry for FOG-2 and MIS was carried out using the antibodies described. FOG-2 protocol was first finished and visualized by DAB with nickel solution (Vector Laboratories) (dark brown appearance) followed by exposure of MIS antibody on the same slides, which was eventually visualized by DAB (light brown appearance). The immunohistochemical and RNA in situ studies were repeated at least three times using tissues from at least three embryos/animals at every given age.
Cell Culture and Transfection Assays
The 293T cells (human embryonic kidney cells) and NIH 3T3 fibroblasts were cultured as previously described [38]. The KK-1 mouse granulosa cell line was established from an ovarian tumor of -inhibin promoter driven SV40-T-antigen transgenic mice [39] and cultured as previously described [40]. Twenty-four hours before transfection, the 293T and KK-1 cells were transferred to 12 wells and the 3T3 cells were transferred to 6 wells, with 3 x 105, 2 x 105, and 2 x 105 cells/well, respectively. The plasmids employed in these assays were -650-MIS-pLUC [41], a -650-bp MIS promoter-luciferase construct (provided by Dr. Holly Ingraham), pMT2-GATA-4 expression vector [37], and pCS2+-FOG-2 expression vector [24] (provided by Dr. Stuart H. Orkin). The 293T and 3T3 cells were transfected with FUGENE6 reagent (Roche Molecular Biochemicals, Mannheim, Germany), and the KK-1 cells were transfected with Lipofectamine reagent (Gibco BRL, Grand Island, NY). The total amount of DNA was 720 ng for 293T cells with 1.5 µl of FUGENE6, 1100 ng for 3T3 cells with 3 µl of FUGENE6, and 2200 ng for KK-1 cells with 7.5 µl of Lipofectamine; 100, 150, and 300 ng of the promoter construct was used, and the total DNA amount was kept constant by adding the corresponding empty expression vector. In all experiments, pCMVß (Clontech, Palo Alto, CA), a ß-galactosidase expression vector, was cotransfected to monitor for transfection efficiency. The cells were harvested 40 h after transfections, and luciferase activity was determined and normalized to the ß-galactosidase activity as previously described [38]. Each experiment was performed in triplicate at least three times to ensure reproducibility. The results were analyzed by ANOVA, followed by a Duncan multiple-range test; P < 0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNOTE ADDED IN PROOFREFERENCES |
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Northern blotting analysis revealed that GATA-4 mRNA is readily detectable in both fetal and postnatal ovaries, whereas the level of FOG-2 mRNA expression was somewhat higher in the fetal (E17) than postnatal ovaries (Fig. 1A). Opposite results were obtained for the testicular samples, in which the level of FOG-2 mRNA expression was higher in the postnatal than fetal samples (Fig. 1B). GATA-4 mRNA was apparent in the testis throughout its development as expected.
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The expression patterns of GATA-4 and FOG-2 mRNAs in the fetal ovaries were further examined by in situ analysis, enabling us to study the earliest stages of mouse gonadogenesis. GATA-4 and FOG-2 mRNAs were evident already in the bipotential urogenital ridge of E10.5 embryos (Fig. 2, A–D), and high levels of both transcripts existed in the ovaries throughout the fetal period (Fig. 2, E–H). Although GATA-4 was expressed only in the ovarian cells, FOG-2 was also apparent in the cells of rete ovarii (Fig. 2, F and H). However, with 32P-labeled RNA in situ analysis we were unable to determine the specific cell types expressing these transcripts. Only background signal was detectable using a control sense probe (Fig. 2, I and J).
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Expression of GATA-4 and FOG-2 Proteins in the Fetal Ovary
Immunohistochemistry enabled us to verify the cell type-specific expression of GATA-4 and FOG-2 proteins. GATA-4 and FOG-2 were detectable in the urogenital ridge cells of both sexes, with no differences between the sexes in the intensity of expression (Fig. 3, A and B). In contrast to earlier findings [12, 16], GATA-4 protein was present in ovaries at late gestation; significant GATA-4 expression was evident in the somatic cells during the entire fetal period, from E12.5 to term (Fig. 3, C, E, and G). Moreover, FOG-2 protein was also evident in the ovarian somatic cells (Fig. 3, D, F, and H). Analysis of parallel sections revealed that the number of cells expressing FOG-2 was somewhat lower than the number of cells expressing GATA-4, but FOG-2 expression persisted in these cells throughout fetal life. All the oocytes remained negative for both GATA-4 and FOG-2. No immunoreactivity was detected when sections were incubated with nonimmune IgG as primary antibody (Fig. 3, I and J).
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Downregulation of FOG-2 in the Fetal Testis
In contrast to ovary, FOG-2 expression was downregulated in the fetal testis, along with the formation of the testicular cords. At E13.5, the testicular structure has been established, so the Sertoli cells can be clearly identified. GATA-4 and MIS proteins were readily detectable in E13.5 Sertoli cells (Fig. 4, A and C), but FOG-2 expression was remarkably weaker (Fig. 4B). Furthermore, double immunohistochemistry for FOG-2 and MIS revealed that FOG-2 was absent in the nucleoli of the MIS-expressing Sertoli cells of E15.5 testis (Fig. 4, D and E). Only cells in the tunica albuginea and a few interstitial cells between the tubuli expressed FOG-2, which is why FOG-2 mRNA was detected in the fetal testis by Northern blotting. We have reported the detailed expression pattern of FOG-2 during testicular development elsewhere [34]. No immunoreactivity was detected with nonimmune IgG as primary antibody.
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Effect of FOG-2 on the Transactivation of MIS Promoter by GATA-4
Given the diverging expression pattern of GATA-4 and FOG-2 in fetal ovaries versus fetal testis, we tested the role of FOG-2 in the regulation of MIS promoter using transient transfection assays. In these studies, we employed a mouse granulosa tumor cell line, KK-1, the endocrinologic characteristics of which resemble those of normal granulosa cells [39], and two heterologous (non-GATA-4, non-FOG-2 expressing) NIH 3T3 and 293T cell lines. The KK-1 cells expressed GATA-4 but not FOG-2 or MIS, as determined by Northern blotting and immunocytochemistry (data not shown). To mirror the situation in vivo as closely as possible, we used a -650-bp fragment of the MIS promoter that harbors potential binding sites for additional activators and repressors. This promoter was active in all three cell lines, as determined by adding the corresponding empty expression vector with the luciferase-driven promoter (Fig. 5). Overexpression of GATA-4 in KK-1 and 293T cells resulted in a 2-fold increase (Fig. 5, A and C; P < 0.01) and in NIH 3T3 cells a 4-fold increase (Fig. 5B; P < 0.01) in MIS promoter activity, whereas FOG-2 alone had no significant (KK-1 and 293T) or at most an enhancing effect (3T3). In 293T cells, FOG-2 had no significant effect on the transactivation of the MIS promoter by GATA-4 (Fig. 5C), but when FOG-2 was overexpressed with GATA-4 in KK-1 and NIH 3T3 cells, the stimulatory effect of GATA-4 was significantly decreased (Fig. 5, A and B; P < 0.01), thus approaching the basal promoter activity.
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Expression of FOG-2 Protein in Postnatal Ovary in Parallel with GATA-4 and MIS
In postnatal ovaries FOG-2 protein was expressed in the granulosa and theca cells of growing follicles, similar to GATA-4 expression (Fig. 6). Differences in the expression of FOG-2 mainly existed between the size and grade of the follicle rather than the age of the animal. In primordial follicles, some of the granulosa cells and a few of the oocytes expressed FOG-2 (Fig. 6B), whereas GATA-4 and MIS expression (Fig. 6, A and C) was negligible. With further activation of folliculogenesis, GATA-4 and MIS were detected in the granulosa cells from the primary follicular stage onward (Fig. 6, D, F, and H). FOG-2 was evident in the granulosa cells, as was GATA-4 and MIS (Fig. 6, E, G, and I), but was also found in the theca cells (Fig. 6, G and I). Although MIS expression diminished with further development and growth of the follicles, FOG-2 was still expressed in most of the granulosa and theca cells of antral follicles (Fig. 6, I and J). Some of these follicles were, however, clearly negative for FOG-2 at this stage. In addition, FOG-2 and GATA-4 were coexpressed in the epithelium lining the ovary (Fig. 6, A, B, and I). In the corpus luteum, GATA-4 expression was apparently downregulated (Fig. 7A), but GATA-6 expression was retained (Fig. 7B). FOG-2 was detectable in most of the luteal cells (Fig. 7C). Sections of the oviduct were also identified adjacent to the ovarian samples; GATA-4 expression was negligible (Fig. 7D) but GATA-6 expression was abundant (Fig. 7E) in the mucosal cells of the oviduct. Again, FOG-2 was clearly coexpressed with GATA-6 rather than with GATA-4 in the cells of the mucosa (Fig. 7F). No immunoreactivity was observed after control staining with nonimmune IgG.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNOTE ADDED IN PROOFREFERENCES |
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Given the presence of GATA-4 in the embryonic gonad of both sexes, and the putative role of GATA-4 in regulating MIS expression, other (inhibitory) factors must exist in the fetal ovary, but not in the fetal testis, to counteract the effect of GATA-4 on MIS. Our results strongly suggest that FOG-2 could act as such a repressor. First, GATA-4 and FOG-2 are colocalized in the developing fetal ovary and restricted to the somatic cells. Second, FOG-2 is able to repress the GATA-4 mediated in vitro transactivation of the MIS promoter. Third, FOG-2 is downregulated in the MIS-expressing Sertoli cells of fetal testis during advancing testicular differentiation, thus allowing GATA-4 to enhance MIS transcription in the late embryonic testis. Although FOG-2 is apparent in the early fetal Sertoli cells, MIS activators other than GATA-4, such as Sox-9 and SF-1, seem to be responsible for the initiation of MIS expression. However, the possible significance of FOG-2 in the early embryonic testis, maybe through its action on gene promoters other than that of MIS, is by no means excluded.
Current evidence suggests that the key factor regulating fetal MIS expression and testicular development is Sox-9 [42, 43]. Introduction of Sox-9 into the gonads of XX mice induces MIS expression, testis formation, and sex reversal of the female reproductive tract [44], whereas MIS expression is totally absent in the testis of XY mice bearing a mutated Sox-9 binding site in the MIS promoter [43]. In addition to GATA-4, Sox-9 interacts directly with SF-1 [45]; mutation of the SF-1 binding site in the MIS promoter results in a significantly reduced level of MIS expression in male mice [43]. Because the potent MIS activator Sox-9 is not expressed in the fetal ovary [46], the role of FOG-2 in repressing MIS expression may not be of ultimate importance. However, both GATA-4 and SF-1 are evident in the fetal ovary, although SF-1 is downregulated by E14.5 [47]. The ability of FOG-2 to repress the GATA-4/SF-1 synergism [33] thus supports our hypothesis that proper FOG-2 expression in the fetal ovary is important for normal development of the female gonadal phenotype. This and other possible actions of FOG-2 need further evaluation by both in vitro and in vivo models.
The action of FOG-2 on MIS regulation was cell specific, indicating that other factors in the granulosa cells or fibroblasts, but not in the kidney cells, are needed. This specificity underscores the importance of using relevant cell lines in in vitro transactivation analyses. The immortalized granulosa cells used in the present study do not entirely reflect the cellular milieu in the somatic cells of early gonads. Nevertheless, our present findings with the MIS promoter are in accordance with previous reports [16, 17, 20, 33], one of which also indicated that the interaction of GATA-4 and FOG-2 is of importance in regulating MIS in the postnatal rat Sertoli cells [33]. Analogously, FOG-2 expression is remarkably upregulated right after birth in the mouse Sertoli cells [34]; at the same time, MIS expression begins to diminish [48]. FOG-2 is thus very likely to be physiologically important in the postnatal testis.
The structure of mouse ovary is less organized before birth, and the specific regulators initiating folliculogenesis after birth are still largely unknown. Nevertheless, the importance of oocyte-derived factors, such as GDF-9, has been discussed [5]. With advancing age and growth, the follicles become responsive to the gonadotropins [5]. Among other factors, gonadotropins regulate expression of the GATA transcription factors in the gonadal cells [12–14, 49], but the factors initiating GATA expression in the gonads remain unknown. In the present transactivation assays, FOG-2 repressed the GATA-4 mediated MIS promoter activity in the KK-1 granulosa tumor cells, which closely resemble normal granulosa cells [39]. However, because the expression pattern of FOG-2 markedly overlapped with that of MIS in the preantral follicles, the importance of FOG-2 in downregulating MIS expression in postnatal granulosa cells remains unclear. As in the early fetal testis, other regulators than GATA-4 are likely responsible for the activation of MIS transcription in the FOG-2-expressing granulosa cells. Thus, further studies, including those on primary granulosa cell cultures, are needed to understand the role of FOG-2 in granulosa and theca cell function. Given its coexpression with GATA-6, FOG-2 may act as a cofactor for additional GATA factors such as GATA-6 in the mammalian reproductive tract.
The results of the present study suggest the GATA cofactor FOG-2 is a regulator of GATA-4 in the developing mouse ovaries. The suggested role of FOG-2 in regulating MIS expression indicates the need for new mouse models to ultimately verify the coordinated functions of FOG-2 and GATA-4 during mouse gonadogenesis in vivo.
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NOTE ADDED IN PROOF |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNOTE ADDED IN PROOFREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Markku Heikinheimo, Program for Developmental and Reproductive Biology, Biomedicum Helsinki, Room B525b, P.O. Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland. FAX: 358 9 4717 1947; markku.heikinheimo{at}helsinki.fi
Received: 20 June 2002.
First decision: 12 July 2002.
Accepted: 25 October 2002.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNOTE ADDED IN PROOFREFERENCES |
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