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Ovary |
State Key Laboratory of Reproductive Biology,3 Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, China
First Affiliated Hospital,4 Nanhua University, Hengyang 421400, China
Department of Biosciences at Novum,5 Karolinska Institute, S-14157 Huddinge, Sweden
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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corpus luteum, follicle, granulosa cells, steroid hormones
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-hydroxylase P450, which catalyses both the 17-hydroxylation and 17,20-lyase reactions in converting progestogens into androgens, and aromatase P450 (P450arom), which converts androgens into estrogens. The steroidogenic enzyme genes display overlapping yet distinct spatial and developmental profiles of expression within ovarian follicles, CLs, and the theca-interstitial region, which suggests that shared but differential mechanisms contribute to the regulated expression of the steroidogenic enzymes [2]. Steroidogenic factor 1 (SF-1), known also as the adrenal-4-binding protein, was originally found as a crucial transcription regulator of steroidogenic enzyme genes [3]. The functional analyses of SF-1 (nuclear receptor [NR] 5A1) showed that the nucleotide sequences recognized by SF-1 were present in all the promoters of the steroidogenic P450 genes [4, 5]. Studies of the regulative mechanisms of steroidogenic transcripts have established that SF-1 is essential for ovarian steroidogenesis [3].
Another member of the nuclear hormone receptor family most closely related to SF-1 is liver receptor homology 1 (LRH-1), also known as CYP7A promoter binding factor, -fetoprotein transcription factor, human B1-binding factor, and NR5A2 [6–9]. LRH-1 and SF-1 share a high degree of structural similarity, notably within regions referred to as the hybrid P box, the A box, and the T box. Because these structures are directly or indirectly implicated in recognition of and interaction with the binding site, Galarneau et al. [10] proposed that both receptors share identical DNA binding mechanisms and specificities. LRH-1 was originally cloned from mouse liver and as a liver-enriched transcription factor has been reported to regulate expression of genes involved in cholesterol metabolism and bile acid synthesis, including cholesterol 7-hydroxylase [7, 11, 12], sterol 12-hydroxylase [13], and the cholesteryl ester transfer protein [14]. Recently, LRH-1 was shown to be even more highly expressed in the ovary, and based on mounting evidence of a functional redundancy between LRH-1 and SF-1, Boerboom et al. [15] proposed that LRH-1 may play a key role in the regulation of ovarian steroidogenic gene expression. However, it is not clear where LRH-1 is localized and produced in the ovary, how expression of LRH-1 changes during the ovarian cycle, how it may be regulated, and what role it may play in ovarian function. To address these problems, the current study was designed to determine the spatial and temporal localization of LRH-1 in the ovaries of immature, cycling, and pregnant rats by in situ hybridization and immunohistochemistry. To explore the regulatory mechanism of LRH-1 in ovarian steroidogenesis, we compared the expression sites of LRH-1 and P450arom in consecutive sections from several ovarian models and raised the possibility that these two genes are potentially linked in a time- and tissue-specific manner in the regulation of ovarian steroidogenic gene expression.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All animals were handled in accordance with the Guidelines for Care and Use of Experimental Animals (Institute of Zoology, Chinese Academy of Sciences). Sprague-Dawley rats were received from Beijing Experimental Animal Center and housed under standardized environmental conditions (14L:10D) with free access to water and pelleted food. At 26 days of age, 15 IU of eCG (Sigma Chemical Company, St. Louis, MO) was administered to the immature animals s.c., and 48 h post-eCG, animals received 15 IU of hCG (Sigma) s.c. to trigger ovulation and luteal development. To determine the estrous cycle patterns of adult rats (2–3 mo), vaginal smears were taken daily from these animals for at least two consecutive estrous cycles. Time-pregnant rats were obtained by normally caging male and female rats overnight. Noon of the day on which a copulatory plug was detected was designated Day 0.5 of pregnancy (P0.5).
Tissue Collections
Immature rats were killed by decapitation at 0 (no eCG) and 48 h post-eCG and at 12 and 24 h after treatment with hCG (n = 3 rats/time point). Cycling rats were killed at 1100 h on the day of proestrus, estrus, metestrus, or diestrus (n = 3 rats/day). Pregnant rats were killed on Days 1, 3, 5, 7, 9, 11, 18, 21, and 22 of gestation (n = 3 rats/day). Ovaries were dissected out immediately, embedded in Tissue-Tek medium (Sakura Finetek, Torrance, CA), and stored at -80°C until processed. Serial sections of 10 µm were prepared with a microtome and mounted on poly-L-lysine-coated slides.
Probes for In Situ Hybridization
Digoxigenin (DIG)-labeled cRNA probes for in situ hybridization analyses were prepared using T7 and T3 (or SP6) polymerases according to the protocol supplied with a kit purchased from Promega (Madison, WI). Both sense and antisense probes were routinely used in all experiments. For LRH-1, a 595-base pair (bp) EcoRI-HindIII fragment was derived from the insert of pf
3 [10] in pBluescript (kindly provided by Dr. Luc Belanger, Centre Hospitalier Universitaire de Quebec, PQ, Canada). For P450arom, a 426-bp fragment was used that corresponds to the 655–1080 nucleotides of P450arom mRNA. For SF-1, a 427-bp fragment was used that corresponds to the 928–1354 nucleotides of SF-1 mRNA. The P450arom and SF-1 fragments were generated by reverse transcription polymerase chain reaction and cloned into pGEM-T easy vector (Promega), respectively.
In Situ Hybridization
The slides with mounted ovarian sections were fixed in 4% paraformaldehyde for 15 min, washed in PBS containing 0.1% active diethyl pyrocarbonate twice for 15 min each, rinsed in 5x saline sodium citrate (SSC: 1x SSC is 0.15 M NaCl, 0.015 M sodium citrate) for 15 min. The slides were then prehybridized with a hybridization mixture (50% deionized formamide, 5x SSC, and 120 µg/ml salmon sperm DNA) without probes for 2 h at 55°C. The DIG-labeled cRNA probes contained in hybridization mixture at a dilution of 400 ng/ml were denatured and applied to hybridization reactions under small pieces of Parafilm (America National Can, Menasha, WI) for 18 h at 55°C. Nonspecifically bound probes were removed by washing slides sequentially at room temperature for 30 min in 2x SSC, at 65°C for 1 h in 2x SSC, and at 65°C for 1 h in 0.1x SSC. The tissue sections were then detected with anti-DIG antibody coupled to alkaline phosphatase according to the manufacturer's instruction (Roche Diagnostics, Hong Kong, China). A sense riboprobe, used as a control for the hybridization specificity and background level, was included for each experiment.
Immunohistochemistry
The antibody was generated from rabbit against the mouse LRH-1 extra-DNA binding domain (kindly provided by Dr. Luc Belanger). The cryosections were prepared as described above. The sections were fixed in 4% paraformaldehyde in PBS, treated with 3% hydrogen peroxide for 10 min, and incubated in blocking solution (10% normal goat serum in PBS) for 10 min at room temperature. Rabbit anti-mouse LRH-1 antibody was applied at a 1:200 dilution to the slides and incubated for 2 h at 37°C. After being washed in PBS, the specimens were treated with biotinylated anti-rabbit IgG antibody and then with horseradish peroxidase (HRP)-streptavidin complex. Signals were detected by adding one to three drops of HRP substrate mixture until desired stain intensity appeared. Preimmune serum (from the same rabbit) was used instead of the first antibody as control.
Classification of Follicles
Cross sections of ovarian follicles were examined using the SPOT digital camera system (Sterling Heights, MI). Follicles were identified as healthy based on morphologic criteria [16]: no more than three pyknotic nuclei in membrana granulosa layer, granulosa cells regularly apposed on an intact basement membrane, and no fibroblastic morphology in the granulosa cell compartment. Follicles were classified as early atretic if they contained more than three pyknotic nuclei and an irregular basal lamina. In addition to these criteria, late atretic follicles also contained fibroblast cells in the granulosa cell compartment, a small number of granulosa cells, and a larger follicular cavity.
Healthy follicles were grouped [2] as very small (40–100 µm), small (101–275 µm), medium (276–450 µm), and large (451–850 µm). Very small follicles were primary follicles up to five granulosa layers. When this class of follicles approached 100 µm in size, theca interna layers started to appear. Small follicles were follicles with theca interna exhibiting the beginning of antrum formation. Medium-sized follicles had a well-developed antrum with the oocyte toward the side of the follicle. Large follicles were those with characteristics of preovulatory follicles. For each ovary, 
12 follicles (2 follicles for each group) were chosen to evaluate the expression of LRH-1 and P450arom genes. A total of 108 follicles (72 healthy and 36 atretic) were studied.
Image Analysis
Hybridization intensity of LRH-1 and P450arom mRNAs in follicles and pregnant CLs was quantified using the computer-aided laser scanning densitometry (Personal Densitometer SI; Molecular Dynamics, Sunnyvale, CA). To make the quantitative difference credible in each ovarian sample, 12 spots were randomly selected in the follicular granulosa layer and the functional CL for the sections hybridized to the antisense and sense probes. Specific hybridization intensity was defined as the average hybridization intensity for a section hybridized to the antisense probe minus the average intensity for the section hybridized to the sense probe. Hybridization intensity was measured as the gray level within a given marked area that was above a preset gray threshold level.
Statistical Analysis
Statistical analysis was performed using Statistical Package for Social Sciences (SPSS for Windows package, release 10.0; SPSS, Chicago, IL). One-way ANOVA was used to evaluate the difference between individual groups, and results were reported as mean ± SEM. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To investigate the potential role of LRH-1 in ovarian function, in situ hybridization analysis was performed to determine which cell types expressed LRH-1 mRNA in ovaries of immature, cycling, and pregnant rats. In the ovary of untreated immature rats, LRH-1 mRNA was restricted to granulosa cells of follicles of different sizes, and the hybridization signal was absent in the interstitial cells (stroma) and theca interna (Fig. 1a, A). Forty-eight hours after eCG (15 IU) treatment, the intensity of LRH-1 mRNA signal increased to a high level, and especially strong staining was found in large antral follicles (Fig. 1a, B and b, P < 0.01). However, the LRH-1 transcripts were hardly detectable in the follicles toward late morphologic atresia (Fig. 1b, P < 0.01). The expression of LRH-1 mRNA was then examined in the ovarian tissue during ovulation and luteinization of eCG-hCG-primed rats. At 12 h after hCG (15 IU) administration, the hybridization intensity of granulosa cells in most follicles was further increased (Fig. 1a, C and b, P < 0.01), but the interstitial cells and theca interna still showed no hybridization signal. At 24 h, some CLs were developed from postovulatory follicles, and the luteinized granulosa cells showed significant hybridization signal (Fig. 1a, D). Figure 1a (E) shows the representative negative control using the LRH-1 sense probe.
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In the ovaries from cycling rats, several ovarian structures were routinely identified within the tissue sections, including follicles, luteinized follicles, newly formed CLs, and old CLs from the previous cycles. These structures were differentiated based on their cellular organization and morphology [17, 18]. New CLs were easily recognizable because they contained an abundance of large luteal cells with a great deal of cytoplasm and the cell nuclei were large and darkly stained. Old CLs from the previous cycles contained fewer luteal cells and consisted primarily of connective tissue and stromal cells. Fig. 2 shows representative LRH-1 mRNA expression patterns observed in cycling rats, but no one image entirely captures all of the expression patterns within the ovary. In the follicles at different developing stages, LRH-1 mRNA was highly expressed in the granulosa layer on all days of the estrous cycle. On estrus, luteinized follicles or newly formed CLs exhibited a strong homogeneous labeling pattern. However, a subset of CLs from previous cycles exhibited a pattern of weak labeling and that was sometimes undetectable depending on the age of the CL (Fig. 2A). The expression of LRH-1 mRNA within new CLs declined during metestrus, although some weak signals remained within some CLs from previous cycles (Fig. 2B). This pattern of labeling was lower or nondiscernible in both most recent and older CLs on diestrus and proestrus (Fig. 2, C and D). Figure 2E shows the representative negative control using the LRH-1 sense probe.
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To further analyze the expression of LRH-1 mRNA in the functional CL, we selected the naturally pregnant rat as a physiological model in which CLs are maintained by endogenous hormones. Fig. 3 shows the LRH-1 probe hybridized to ovarian tissues collected from the rats at different periods of pregnancy. LRH-1 mRNA was highly expressed in newly forming CLs during the initiation of pregnancy (Fig. 3a, P1 and P3, b) but decreased dramatically and became hardly detectable on Day 7 of pregnancy (P < 0.01). However, expression of LRH-1 mRNA increased again on Day 9 and remained at a high level on Day 11 of gestation (P < 0.01). During the later period of pregnancy, the signal for LRH-1 mRNA expression decreased to a very low level and was hardly detectable on Day 21 of gestation (Fig. 3b, P < 0.01). In contrast, the granulosa cells of follicles of different sizes exhibited strong and constitutive expression of LRH-1 mRNA throughout the entire pregnancy.
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LRH-1 Protein Expression in the Rat Ovary
Immunohistochemical staining for LRH-1 showed that the localization of LRH-1 protein was similar to that of its mRNA and was primarily restricted to granulosa and luteal cells of different ovarian models. Figure 4 shows representative LRH-1 protein expression patterns. In these ovarian models, LRH-1 protein was constantly detected in the granulosa cells of follicles of different sizes and in the CLs on all days of the estrous cycle. In contrast to the biphasic change of mRNA, the pattern for LRH-1 protein expression was persistent in the functional CLs during the entire pregnancy. High-power views revealed immunohistochemical staining for LRH-1 protein predominantly localized in nuclear compartments (Fig. 4B), whereas the cytoplasmic localization was also seen in some granulosa and luteal cells. In Figure 4, I is the representative negative control using preimmune serum.
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Differential Colocalization of LRH-1 and P450arom mRNAs in Serial Ovarian Sections
Based on the above results and on previous reports [19], it seems most likely that LRH-1 and P450arom were coexpressed in the relevant endocrine cell lineages of rat ovary. We therefore compared their expression sites in cross sections of different ovarian models.
Most genes exhibit follicle-selective expression patterns dependent on particular development stages. In the ovary of the untreated immature rat, granulosa cells in the majority of follicles were labeled for LHR-1 mRNA, whereas the transcript of P450arom was only present in a minority of follicles (Fig. 5a, A1 and A2). In the eCG-induced ovary, P450arom mRNA was primarily expressed in a few large antral follicles (Fig. 5b, E2 and c, P < 0.01). In sections of cycling ovary, some large antral or preovulatory follicles also showed coincident expression signals for LRH-1 and P450arom mRNAs (Fig. 5a, B1 and B2, C1 and C2).
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To determine whether the changes in P450arom mRNA content in CLs were associated with that of LRH-1 mRNA, consecutive sections of rat ovaries were used to compare their expression patterns throughout the pregnancy process. P450arom mRNA in CLs was at low to undetectable levels during Days 1–5 of pregnancy (Fig. 6a, P1, P3 and P5, b). In contrast, LRH-1 mRNA was strongly expressed on Days 1 and 3 of pregnancy before a detectable decrease on Day 5 (P < 0.01). During the middle phase of pregnancy, the two genes exhibited overlapping expression (Fig. 6a, P9 and P11). By Day 18 of pregnancy, the level of LRH-1 mRNA decreased dramatically (P < 0.01) whereas P450arom mRNA was expressed at moderate levels until Day 21 (Fig. 6b). On Day 22 (postpartum), both LRH-1 and P450arom mRNAs declined to undetectable levels. In Figure 6a, C is the representative negative control using LRH-1 and P450arom sense probes.
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Comparison of Expression Patterns Between LRH-1 and SF-1 in Rat Ovary
Although recent data [15] suggested a functional redundancy between LRH-1 and SF-1, in the present study these two genes exhibited different expression patterns in rat ovarian tissue. In situ localization results (Fig. 7) indicated that SF-1 mRNA was primarily expressed in theca interna and interstitial tissue, with very low levels in granulosa cells and CLs (Fig. 7, A1, B1, and C1). In contrast, LRH-1 mRNA was present at high levels in granulosa cells and CLs of pregnancy, with no signal observed in theca or stroma (Fig. 7, A2, B2, and C2). In Figure 7, D1 and D2 are the representative negative controls using SF-1 and LRH-1 sense probes.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This report is the first to demonstrate the mRNA and protein expressions of LRH-1 at different compartments and levels in rat ovarian tissues. LRH-1 mRNA and protein are primarily, if not exclusively, localized to the granulosa cell layer and CL, and levels of expression change in a stage-specific manner in ovaries of immature, cycling, and pregnant rats. This expression pattern for LRH-1 raises the obvious question of its specific role in follicular and luteal functions. Based on the mounting evidence of a potential functional redundancy between SF-1 and LRH-1, we propose that LRH-1 plays a key role in the regulation of gonadal steroidogenic gene expression. The transcripts for some steroidogenic genes, such as steroidogenic acute regulatory protein, P450scc, and P450arom, are induced in granulosa cells during follicular development [2, 19, 20]. Although our data indicate that LRH-1 is present in follicles of different sizes, a marked increase in the mRNA and protein levels was observed in the large antral follicles from eCG-primed rats, whereas late atretic follicles had a weak signal or were devoid of LRH-1 transcripts. During ovulation and luteinization, LRH-1 mRNA is maintained at a high level in granulosa-luteal cells until early luteal formation. These findings support a putative mechanism for the transcriptional upregulation of steroidogenic genes in granulosa-luteal cells, in which the level of LRH-1 expression represents an important regulatory factor in addition to the function provided by SF-1.
In a very recent study [21], LRH-1 was equivalent or even superior to SF-1 in regulation of P450arom expression in transfection assays of in vitro granulosa cells. However, little is known about the localization patterns and potential links between LRH-1 and P450arom in ovarian endocrine cells. We showed that both LRH-1 and P450arom mRNAs are sometimes coexpressed in granulosa and luteal cells of different ovarian models. The LRH-1 mRNA was abundant in follicles of different developmental stages and increased as follicular maturation progressed, whereas the P450arom transcript was expressed primarily in tertiary and Graafian follicles of eCG-primed or mature rats. LRH-1 expression precedes that of P450arom in granulosa cells during follicular development. Because mechanisms other than regulation of LRH-1 expression may come into play to regulate expression of P450arom in rat granulosa cells and are likely to include posttranslational modification and activation of LRH-1 by potential ligand and cofactors, these findings support in part the hypothesis that LRH-1 is an essential upstream regulator of P450arom expression. However, the nonparallel expression patterns between LRH-1 and P450arom also led us to speculate that LRH-1, like SF-1, may be a multifunctional factor regulating several steroidogenic genes, including P450arom. In the ovary of the pregnant rat, the variations in mRNA levels between these two genes were found in early and late CLs, whereas approximately parallel expression signals for LRH-1 protein and P450arom transcript were present throughout the gestation process. The variation between the protein and mRNA levels of LRH-1 may arise from the different processes and mechanisms for protein synthesis and degradation. These findings, to a certain extent, support the hypothesis that LRH-1 regulates ovarian P450arom expression in a time- and tissue-specific manner.
Clyne et al. [22] recently reported that LRH-1 regulates expression of the P450arom gene in preadipocytes. Because LRH-1 but not SF-1 is expressed in breast adipose [22] and cancer tissue [23], Clyne et al. [22] proposed that LRH-1 represents a certain regulator of local estrogen biosynthesis in the breast. Although both LRH-1 and SF-1 were present in ovary, the distinct tissue distributions between them lead us to propose different functions in ovarian steroidogenesis. As previously reported [24–26], SF-1 was abundantly expressed in cells of ovarian theca interna and interstitial tissue at which androgens are produced, with very low levels in granulosa cells and CLs. In contrast, LRH-1 was present at high levels in granulosa-luteal cells, from which estrogens are synthesized, with no signal observed in theca or stroma. These findings are in agreement with a brief report [21] in mouse that LRH-1 may play a critical role in P450arom regulation in the ovary.
We reported here the spatiotemporal expression patterns of LRH-1 in rat ovary and explored the implication of LRH-1 in ovarian steroidogenesis. The presence of similar DNA binding domains in LRH-1 and SF-1 structures raises the possibility that LRH-1, like SF-1, may be involved in the regulation of steroidogenic genes other than P450arom. Future studies will be required to demonstrate that LRH-1 can transactivate other steroidogenic target genes in granulosa-luteal cells and that gonadal expression of this nuclear receptor is conserved in other species.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Cheng Zhu, State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 25 Beisihuan Xilu, Zhongguancun, Beijing 100080, People's Republic of China. FAX: 86 10 62529248; zhuc{at}panda.ioz.ac.cn
Received: 25 September 2002.
First decision: 25 October 2002.
Accepted: 24 March 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 
, and 
) differ within each panel (P < 0.05)
