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Hormone Research Center (J.-I.P., H.-J.P., H.-S.C., K.L., S.-Y.C.) and Department of Biology (H.-J.P), Chonnam National University, Kwangju 500–757; and Department of Aquaculture, Yosu National University (W.-K.L.), Chonnam 550–749, Republic of Korea
Address all correspondence and requests for reprints to: Dr. Sang-Young Chun, Hormone Research Center, Chonnam National University, Kwangju 500–757, Republic of Korea. E-mail: sychun{at}chonnam.chonnam.ac.kr
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-amanitin, but was superinduced by
cycloheximide. Furthermore, treatment of adult cycling rats with
pentobarbital abolished NGFI-B expression on proestrus, and exogenous
administration of hCG restored it, indicating the role of the
preovulatory surge of LH in the stimulation of NGFI-B expression. These
results demonstrate the cell type-specific expression and gonadotropin
induction of NGFI-B in granulosa cells of preovulatory follicles and
suggest a role for NGFI-B in the ovulatory process. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NGFI-B is widely expressed at relatively high levels in the brain,
adrenal gland, muscle, and gonads (1, 11, 12). Stress
induces NGFI-B expression in CRH neurons (13, 14) and
adrenal cortex (15). In addition, NGFI-B regulates the
expression of genes encoding steroidogenic enzymes in adrenal such as
21-hydroxylase (16), suggesting that NGFI-B may play a
dynamic role in the function of the
hypothalamic-pituitary-adrenocortical axis. T cell receptor-induced
apoptosis is blocked by overexpression of a dominant negative mutant of
NGFI-B (17, 18, 19), suggesting that NGFI-B may act as a
central mediator of the signaling pathway controlling apoptosis in T
cells. In the ovary the expression of NGFI-B messenger RNA (mRNA) in
unspecified ovary (12) and in corpora lutea
(20) has been reported. Moreover, a recent report
demonstrates the induction of 20-hydroxysteroid dehydrogenase
expression by NGFI-B during PGF2-mediated
luteolysis (21). However, localization and hormonal
regulation of NGFI-B expression during ovarian follicle development
have not been demonstrated.
The present study demonstrates the cell type-specific localization and gonadotropin regulation of NGFI-B expression during ovarian follicle growth in gonadotropin-primed immature and adult cyclic rats. The results show the temporal and spatial patterns of NGFI-B mRNA expression in granulosa cells of preovulatory follicles during a periovulatory period.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-amanitin, cycloheximide, and pentobarbital were
purchased from Sigma (St. Louis, MO). Female rats of the Sprague Dawley strain were purchased from Daehan Laboratories (Chungbuk, Korea). They were housed in groups in a room with controlled temperature and photoperiod (10 h of dark, 14 h of light, with lights on from 0600–2000 h). The animals had ad libitum access to food and water. The animals, ranging in age from 1–21 days, were killed by cervical dislocation, and the ovaries were removed for RNA analysis. Ovaries were also collected from immature (26-day-old) rats at various times after treatment with 10 IU PMSG to induce multiple follicle growth. Some rats received a single ip injection of 10 IU hCG to induce ovulation, and ovaries were obtained at different time intervals for Northern blot and in situ hybridization analyses. Adult female rats (200–250 g) were maintained as described above. Estrous cycle stages were determined by daily examination of vaginal cytology. Only animals that showed at least two consecutive 4-day cycles were used. Rats were killed by cervical dislocation, and the ovaries were removed at 0900 h on each day of the cycle as well as at 1800 and 2000 h on proestrus. Ovaries were frozen rapidly on dry ice for RNA isolation or were fixed for in situ hybridization analysis. Some rats were injected ip with pentobarbital (40 mg/kg in saline) to block the endogenous LH surge or with vehicle alone at 1330 h on proestrus. Two of the pentobarbital-treated rats received a single injection of 10 IU hCG at 1630 h on proestrus. The animals were killed for analysis at 1800 h on proestrus.
Northern blot analysis
Total RNA from ovaries or cultured follicles were isolated using
Tri-Reagent solution (Molecular Research Center, Inc.,
Cincinnati, OH). Ten or 20 µg total RNA were fractionated by
electrophoresis on a 1.2% agarose gel containing formaldehyde and
transferred to nylon membranes by capillary blotting with 20 x
SSC (sodium citrate-sodium chloride). After UV cross-linking and
prehybridization, membranes were hybridized overnight at 42 C in a
solution containing 50% formamide, 5 x SSC, 1.6 x
Denhart’s solution, 1 mM EDTA, 250 µg/ml denatured
herring sperm DNA, 500 µg/ml yeast transfer RNA, and a total of
2–4 x 106 cpm of a
32P-labeled rat NGFI-B complementary DNA (cDNA)
probe containing ligand-binding domain region (2). After
hybridization, membranes were washed twice for 5 min each time at room
temperature in 2 x SSC and 0.1% SDS, followed by 1 h at 65
C in 0.5 x SSC and 0.1% SDS. Membranes were then exposed using
Kodak RX films (Eastman Kodak Co., Rochester,
NY) for 1 day at -80 C. For normalization of data, blots were stripped
by boiling in 0.1 x SSC and 0.5% SDS twice for 20 min each time
before reprobing with a full-length cDNA probe for rat
glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) subcloned into pTRIPLE
(Ambion, Inc., Austin, TX). The band intensities were
subsequently measured using a phosphorimager (Bio-Rad Laboratories, Inc., Hercules, CA), and the signals were
normalized to the GAPDH internal control.
In situ hybridization analysis
Ovaries or cultured follicles were fixed at 4 C for 6 h in
4% paraformaldehyde in PBS, followed by immersion in 0.5 M
sucrose in PBS overnight. Cryostat sections (14-µm thick) were
mounted on poly-L-lysine (Sigma)-coated
microscope slides, fixed in 4% paraformaldehyde in PBS, and stored at
-80 C until analyzed. The hybridization procedure was essentially the
same as previously described (22). In brief, sections were
pretreated serially with 0.2 M HCl, 2 x SSC, pronase
E (0.125 mg/ml; Sigma), 4% paraformaldehyde, and acetic
anhydride in triethanolamine. Hybridization was carried out at 52-55 C
overnight in the mixture containing 35S-labeled
rat NGFI-B complementary RNA (cRNA) probe (108
cpm/ml) corresponding ligand-binding domain region, 50% formamide, 0.3
M NaCl, 10 mM Tris-HCl, 5 mM EDTA,
1 x Denhardt’s solution, 10% dextran sulfate, 1 µg/ml carrier
transfer RNA, and 10 mM dithiothreitol. Posthybridization
washing was performed under stringent conditions that included
ribonuclease A (25 µg/ml) treatment at 37 C for 30 min and a final
stringency of 0.1 x SSC. Slides were dipped into NTB-2 emulsion
(Eastman Kodak Co., Rochester, NY), exposed at 4 C, and
developed after 2 weeks. The slides were stained with hematoxylin and
eosin and examined under the light microscope with bright- and
darkfield illumination.
Follicle culture
Preovulatory follicles (>800 µm in diameter) were dissected
by fine forceps from ovaries collected at 48–52 h after PMSG
injection, and follicle culture was performed as previously described
(22). Fifteen to 20 follicles were cultured in glass vials
containing 300 µl MEM (Life Technologies, Inc., Grand
Island, NY) supplemented with penicillin, streptomycin,
L-glutamine, and 0.1% BSA (wt/vol; fraction V,
Sigma) in the absence or presence of different hormones.
Cultures were maintained for up to 24 h at 37 C under 5%
CO2-95% O2. After
incubation, follicles were snap-frozen for RNA isolation or fixed for
in situ hybridization analysis.
Western blot analysis
Cultured preovulatory follicles were lysed by homogenization in
buffer containing 50 mM Tris-HCl (pH 7.4), 1% Nonidet
P-40, 0.25% sodium deoxycholate, 150 mM NaCl, 1
mM EGTA, 1 mM phenylmethylsulfonyfluoride, 1
µg/ml aprotinin, 10 µg/ml leupeptin, and 1 mM NaF. The
lysates were centrifuged at 13,600 x g to precipitate
the membrane fraction, and the supernatant was collected for the
analysis. Protein concentrations were determined by using bicinchoninic
acid protein assay (Pierce Chemical Co., Rockford,
IL).
Follicle cell lysates (100 µg protein) were loaded onto a 10% continuous gradient SDS-polyacrylamide gel, and proteins were transferred to nitrocellulose membranes (Amersham Pharmacia Biotech, Arlington Heights, IL). Nitrocellulose membranes were blocked with TBST [10 mM Tris-buffered isotonic saline (pH 7.0), 0.1% merthiolate, and 0.1% Tween-20] buffer containing 5% nonfat dry milk for 30 min at room temperature with shaking. Blots were then incubated with primary antibody (anti-Nur77 at 0.5 µg/ml dilution; PharMingen, San Diego, CA) in TBST buffer for 24 h at 4 C with gentle shaking. Blots were washed twice in TBST for 10 min each time and incubated with antimouse IgG conjugated to alkaline phosphatase (1:1000 dilution; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) in TBST for 1 h at room temperature. After washing twice in TBST, blots were analyzed with the Western-Star chemiluminescence detection system (Tropix, Inc., Bedford, MA) according to the manufacturer’s guidelines.
Data analysis
Statistical differences were assessed by one-way ANOVA, followed
by Student’s t test. P < 0.05 was
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(left panel), the 2.9-kb
transcript was detected in the ovary as well as the hypothalamus. The
levels of ovarian NGFI-B transcript were markedly increased in
12-day-old rats and remained high until animals were 21 days of
age.
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(middle panel), PMSG treatment of 26-day-old
immature rats caused a gradual decrease in ovarian NGFI-B expression.
Quantitative analysis of ovarian NGFI-B signals (Fig. 1B, left
panel) showed a 75% decrease (P < 0.05) 48
h after PMSG treatment. Treatment of PMSG-primed rats with hCG,
however, resulted in the rapid and transient stimulation of NGFI-B mRNA
expression, reaching a maximum stimulation 1 h after hCG treatment
(Fig. 1A, right panel). The levels of NGFI-B mRNA declined
to control levels (0 h) by 9 h after treatment. Quantitative
analysis (Fig. 1B, right panel) revealed that hCG treatment
resulted in 9.5- and 5.2-fold increases (P < 0.05) in
ovarian NGFI-B mRNA by 1 and 3 h, respectively. In addition to a
major size of 2.9 kb, the 6.6- and 3.7-kb transcripts were also
detected in ovaries expressing high levels of NGFI-B (Fig. 1A, right panel), as found in kidney cells
(23).
To determine the cell types expressing NGFI-B mRNA, in situ
hybridization was performed on ovarian sections obtained from immature
rats treated with gonadotropins. NGFI-B mRNA was detected in thecal
cells of growing follicles in the ovaries of untreated immature rats
(Fig. 2, A, B, D, and E). In the ovaries
obtained 2 days after PMSG treatment, NGFI-B signals were detected in
thecal cells of preovulatory follicles as well as growing follicles
(Fig. 2, F, G, I, and J). In the ovaries of immature rats primed with
PMSG, followed by hCG stimulation for 1 h, NGFI-B mRNA was
detected in granulosa and interstitial cells as well as in thecal cells
(Fig. 2, K, L, N, and O). High levels of NGFI-B mRNA were detected in
the granulosa cells of preovulatory follicles, but not growing
follicles (Fig. 2, N and O). No specific signal was detected in ovarian
sections hybridized with sense probe (Fig. 2, C, H, and M).
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). Quantitative analysis (Fig. 3B)
showed that LH treatment produced a 13-fold increase (P
< 0.05) in follicular NGFI-B mRNA by 1 h. The levels of NGFI-B
mRNA gradually declined to control levels (0 h) by 9 h after LH
treatment. As shown in Fig. 3C, LH treatment for 1 h stimulated
NGFI-B mRNA in a dose-dependent manner, reaching saturating levels at
100 ng/ml. To determine the site of NGFI-B mRNA expression in cultured
preovulatory follicles, in situ hybridization was performed
on sections of follicles collected before culture or cultured in the
presence of LH for 1 h. NGFI-B signals were detected in thecal
cells, but not granulosa cells, of preovulatory follicles collected
before culture (Fig. 4, A and B). In
follicles cultured with LH for 1 h, however, NGFI-B signals were
also detected in granulosa cells as well as in thecal cells (Fig. 4, C
and D). No specific signal was detected in follicles hybridized with
sense probe (data not shown).
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, the levels of NGFI-B
protein were greatly increased within 1 h and remained high
3 h after LH treatment. LH-stimulated NGFI-B ranged in size from
approximately 70 up to 90 kDa, possibly due to heavy phosphorylation of
the NGFI-B protein, as demonstrated previously in NGF-treated PC12
cells (5).
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-amanitin, an RNA polymerase II inhibitor, or
cycloheximide, a protein synthesis inhibitor. Treatment with
-amanitin blocked LH-stimulated NGFI-B expression in a
dose-dependent manner, an 82% decrease (P < 0.05) at
25 µg/ml (Fig. 6, left
panel). In contrast, inclusion of cycloheximide enhanced the
stimulatory effect of LH on NGFI-B expression, a 1.8-fold increase
(P < 0.05) at 10 µg/ml (Fig. 6, right
panel). Treatment of follicles with cycloheximide alone resulted
in a minimal stimulation of NGFI-B expression.
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, NGFI-B transcripts were greatly
stimulated at 1800 and 2000 h on proestrus, during which the peak
of the preovulatory LH surge occurs (24). To further
assess the role of the preovulatory LH surge in NGFI-B stimulation,
some rats were treated with pentobarbital at 1330 h on proestrus
to block the endogenous LH surge. Treatment of the animals with
pentobarbital abolished NGFI-B mRNA stimulation at 1800 h on
proestrus, whereas saline treatment had no effect (Fig. 7B).
Furthermore, the inhibitory effect of pentobarbital on NGFI-B mRNA
expression was reversed by the exogenous administration of hCG,
indicating that NGFI-B mRNA is rapidly stimulated in response to the
preovulatory LH surge.
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, A–F). Corpora lutea
also expressed low levels of NGFI-B mRNA. In the ovaries collected at
1800 h on proestrus, NGFI-B mRNA was detected in the granulosa
cells of preovulatory follicles, but not growing follicles (Fig. 8, G–L). Interstitial cells as well as thecal cells also expressed NGFI-B
mRNA. No specific signal was detected in ovarian sections hybridized
with sense probe (Fig. 8, C and I).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NGFI-B is a nuclear receptor encoded by an early response gene that is rapidly induced in cells stimulated with growth factors and/or other extracellular ligands. ACTH treatment rapidly increases levels of NGFI-B mRNA within 1–2 h in both the adrenal gland (15) and the adrenocortical tumor cell line Y1 (16). Similarly, CRH stimulates NGFI-B expression within 1 h in pituitary-derived AtT-20 cells, which regulates the transcriptional activity of the POMC gene (27). In the ovary induction of NGFI-B expression by LH/hCG in granulosa cells of preovulatory follicles was rapid and transient, a pattern consistent with immediate-early induction of this gene in other cells. A recent study demonstrates that early growth response protein-1, one of the immediate-early transcription factor genes, is also rapidly induced in an ovulatory follicle in response to gonadotropins (28). As with many other immediate-early genes, the rapidly induced ovarian NGFI-B may regulate the expression of a specific gene(s) associated with ovulation, and thus play an important role in the ovulatory process.
The preovulatory surge of LH is obligatory to trigger the ovulatory
process (including follicle rupture, oocyte maturation, and
luteinization) (29). Although the biochemical cascade that
leads to ovulation is largely unknown, several studies have shown that
the LH surge stimulates the expression of a number of specific genes
associated with ovulation, including progesterone receptor, PG
endoperoxide synthase, cytochrome P450 side-chain cleavage
enzyme, and 17-hydroxylase (30). NGFI-B
binds as a monomer to a specific response element (NBRE) (7, 31), which consists of a half-site estrogen response element
preceded by two additional 5'-adenine nucleotides (AAAGGTCA). Indeed,
NGFI-B has been shown to stimulate the transcriptional activity of
hydroxylase genes, the rat P450c21 (16, 32) and the mouse P450c17
(33), leading to increased synthesis of cortisol and
androgen, respectively. A recent study shows that NGFI-B enhances the
transcriptional activity of another steroidogenic gene,
20-hydroxysteroid dehydrogenase, which encodes an enzyme with
dehydrogenase activity and causes the catabolism of progesterone
synthesized in the corpus luteum (21). In addition,
similar NBRE sequences are present in the promoters of genes encoding
several other steroidogenic enzymes, including CYP11A1, CYP11B1, and
CYP19 (aromatase) (34, 35). Thus, it is most likely that
NGFI-B induced by the LH surge may regulate the transcriptional
activity of ovarian steroidogenic gene(s) and thereby play a role in
ovulation.
Despite the well established role of NGFI-B in many processes, mice deficient in NGFI-B have no apparent phenotype of organs, including the ovary, suggesting that other members of the same subfamily of nuclear receptors are sufficient to maintain normal functions by a compensatory mechanism (36, 37). Indeed, two other NGFI-B family members, Nurr1 (38) and Nor1 (39), may compensate for the loss of NGFI-B. Both Nurr1 and Nor1 share extensive homology with NGFI-B in their DNA-binding domains, zinc fingers, and A box. Furthermore, these three proteins, when acting as monomers, bind to the same NBRE (7). Nurr1 and Nor1 can trans-activate through the same DNA element as NGFI-B, and their trans-activation activities can be blocked by a NGFI-B dominant negative protein in T cell apoptosis, demonstrating functional redundancy (19). Nor1 has been shown to activate the expression of the P450c21 gene through its interaction with NBRE promoter sequences in the adrenocortical tumor cell line Y1, indicating that Nor1 may substitute for NGFI-B function (40). It remains to be determined whether ovarian Nurr1 or Nor1 is overexpressed by a compensatory mechanism and performs a similar function as NGFI-B in NGFI-B-deficient mice.
Western blot analysis showed that LH/hCG induces a wide range of NGFI-B protein in preovulatory follicles (70 up to 90 kDa), possibly due to heavy phosphorylation of the NGFI-B protein. Several lines of evidence suggest that NGFI-B activity may also be regulated through phosphorylation. NGFI-B from phorbol 12-myristate 13-acetate-stimulated T cells can be seen as a protein species of 70 kDa, whereas inomycin-stimulated NGFI-B ranges in size from approximately 70 up to 90 kDa (41). NGFI-B is phosphorylated in vivo on multiple sites in the amino-terminus, which is primarily responsible for the trans-activation activity (8). Phosphorylation of NGFI-B at Ser354, a site within a region essential for sequence-specific DNA binding, decreases DNA binding affinity (42). A recent study demonstrates that NGF induces the phosphorylation of Ser105 of NGFI-B in PC12 pheochromocytoma cells, resulting in translocation of the NGFI-B-RXR heterodimer complex out of the nucleus (43). Taken together, these observations suggest that phosphorylation may play an important role in regulating NGFI-B function in the ovary.
Induction of NGFI-B by LH in in vitro cultured preovulatory
follicles was blocked by -amanitin, but superinduced by
cycloheximide. Induction of NGFI-B by LH may be primarily due to the
rapid transcriptional activation of the NGFI-B gene. It has been
reported that inducible expression directed by the first 86 nucleotides
of the NGFI-B promoter closely mimics that of the endogenous gene and
does not require de novo protein synthesis
(44). The superinduction of LH-stimulated NGFI-B mRNA
levels by cycloheximide may be due to increased mRNA stability or
enhanced transcription. Different mRNAs are degraded based on specific
5'- and 3'-noncoding sequences (45). Alternatively,
cycloheximide treatment may decrease the levels of a repressor
protein(s) that acts on the enhancer sequences at the NGFI-B promoter
region. Indeed, the enhanced expression of the NGFI-B gene by
cycloheximide has been demonstrated in skeletal muscle cells
(46). Therefore, it is plausible that the rapid induction
of NGFI-B by LH in preovulatory follicles would be associated with
increased NGFI-B mRNA and transcription of NGFI-B gene.
NGFI-B was also expressed in thecal cells in follicles of different sizes. Because apoptosis of atretic follicles in rodents is confined to granulosa cells (47), the constitutive expression of NGFI-B in thecal cells may be responsible for the scarcity of thecal cell degeneration in rats. However, NGFI-B has been shown to be necessary for the induction of apoptosis in T cells (17, 18). Alternatively, NGFI-B may play a role in thecal cell differentiation. Our observation of a marked increase in levels of NGFI-B expression at 12 days of age suggests the involvement of NGFI-B in thecal cell differentiation. Ovaries of rats before 12 days of age mainly contain nongrowing and small growing follicles that undergo an extensive differentiation of thecal cells (48). LH/hCG treatment also induced the expression of NGFI-B in interstitial cells. Because the pattern of NGFI-B expression seems to follow the spatial expression of cytochrome P450 side-chain cleavage enzyme (49) and steroidogenic acute regulatory protein (50) in cells engaged in steroidogenic activity, NGFI-B expression in the thecal and interstitial cells may be correlated with terminal commitment of cells for steroidogenic differentiation.
In summary, the present study shows the cell-type specific expression and gonadotropin regulation of NGFI-B mRNA during follicle development. NGFI-B is expressed in thecal cells of growing and mature follicles. LH/hCG treatment induces the rapid expression of NGFI-B in granulosa cells of preovulatory follicles both in vivo and in vitro. Furthermore, the preovulatory LH surge in adult cycling rats is necessary for the induction of NGFI-B mRNA in granulosa cells of preovulatory follicles. The present results suggest that NGFI-B may play a role in ovulation by initiating a cascade of ovulation-specific gene expression in ovulatory follicles in response to the LH surge.
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Acknowledgments |
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Footnotes |
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Received December 7, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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induced
expression of 20-hydroxysteroid dehydrogenase involves the
transcription factor Nur77. J Biol Chem 275:37202–37211 subunit
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