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Department of Biochemistry, North Carolina State University, Raleigh, North Carolina 27695-7622
Address all correspondence and requests for reprints to: Dr. William L. Miller, Department of Biochemistry, Box 7622, North Carolina State University, Raleigh, North Carolina 27695-7622.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Another activator of FSHß synthesis is GnRH. Evidence that GnRH regulates FSHß gene expression comes from studies in which a GnRH antagonist or passive immunoneutralization to GnRH caused a dramatic decrease in FSHß mRNA levels (8). The effect of GnRH on FSHß synthesis is at least partly at the transcriptional level, because using a nuclear run-off assay, GnRH was shown to increase the transcriptional rate of the FSHß gene (9). GnRH is released from the hypothalamus and binds to a G protein-coupled receptor in pituitary gonadotropes where FSHß is expressed. Upon receptor binding, GnRH activates a GTP-binding protein (Gq/G11), which results in enhanced phosphoinositide turnover, leading to calcium mobilization and protein kinase C activation (10). Recently, GnRH has also been shown to activate mitogen-activated protein kinase (11), which is important for GnRH stimulation of the FSHß mRNA levels (12).
Although activin and GnRH have been shown to increase FSHß gene transcription, the molecular mechanisms by which activin or GnRH regulate FSHß gene transcription are not known. Recently, two activator protein-1 (AP-1) sites (at -120 and -83 bp) in the proximal promoter of the ovine FSHß gene were shown to be important for increasing FSHß gene expression (13). Using an in vitro cell system that involves cotransfection of GnRH receptors with the oFSHßLuc constructs into HeLa cells, it was found that GnRH increases oFSHß gene transcription through these two AP-1 sites (14). However, it is not clear whether this can occur in a gonadotrope. In the case of activin, no in vitro test model for activin stimulation of FSHßLuc has been developed to determine whether the two AP-1 sites participate in activin action.
Previously, transgenic mice were generated that carry the oFSHß promoter (-4741 to +759 bp) linked to a luciferase reporter gene. This oFSHßLuc transgene was expressed uniquely in gonadotropes and regulated in an FSHß-specific manner, as shown in the companion paper (14A ). To test the physiological relevance of the two proximal AP-1 sites in mediating GnRH and/or activin action in gonadotropes, transgenic mice were generated that contain the oFSHß promoter lacking functional -120 and -83 bp AP-1 sites. Using pituitary cell cultures from transgenic mice that carry the wild-type or AP-1 mutant transgene, the importance of -120 and -83 AP-1 sites in GnRH induction in gonadotropes has now been confirmed in this report. Furthermore, activin stimulation of an FSHßLuc construct in primary gonadotropes was demonstrated for the first time, and the data suggest that the AP-1 sites are not necessary for activin action.
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Materials and Methods |
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Transgenic mice
Mice containing the wild-type oFSHßLuc transgene have been
characterized previously (14A ). Liberation of the
mut-oFSHßLuc transgene fragment from its plasmid (see above) for
preparation of transgenic mice was accomplished by digestion with
BamHI/KpnI. Transgenic mouse production,
identification, and characterization of tissue-specific expression were
performed as previously reported (14A ). Mice that carry
the mutation (mut) transgene were identified by PCR using the same
primer sets previously used for the pGL3-based wild-type (wt) transgene
(14A ). The data shown in this study used either male or
female transgenic mice, because we performed our experiments using
exclusively male or female mice and found no difference in their
responses to antibodies or hormones (anti-GnRH, follistatin, activin,
or GnRH) in vivo or in pituitary cultures.
In vivo experiments
All of the in vivo experiments, including castration,
Lupron treatment, and estrous cycle studies, followed the procedures
previously reported (14A ). For GnRH antiserum experiments,
200 µl GnRH antiserum (15) were injected ip daily for 3
days, and pituitary luciferase activity was measured. All animal
experiments were performed in accordance with the rules and regulations
of the North Carolina State University institutional animal care and
use committee.
Primary pituitary cell cultures
Pituitaries were removed from transgenic mice 7 weeks old or
older and then dispersed into single cell suspensions as described
previously (14A ). Briefly, the pituitaries were cut into
small fragments and digested with collagenase (Sigma, St.
Louis, MO) for 1.5 h and then with pancreatin (Life Technologies, Inc., Grand Island, NY) for 15 min. Cells were
washed and resuspended in medium 199 containing 10% charcoal-treated
sheep serum, insulin, and antibiotics. Cell yields were 0.3–0.6
x 106/pituitary. Cells were plated in 96-well
plates at 30,000–60,000 cells/well and allowed to attach for 1–2
days.
For activin and/or GnRH treatments, mouse pituitary cell cultures were first treated with 250 ng/ml follistatin for 16 h. Follistatin was then withdrawn, cells were washed, and media (containing 1% serum) with or without activin and/or GnRH were added. Four to 6 h after activin/GnRH addition, media were removed, and 50 µl of Passive Lysis Buffer (Promega Corp.) were added. Lysate (35 µl) was assayed for luciferase activity.
Hormones and antiserum
Recombinant human follistatin and recombinant human activin A
were provided by the National Pituitary and Hormone Program of the
NIDDK. GnRH was obtained from Sigma. Anti-GnRH serum (from
pig) was a gift from Dr. Traywick (North Carolina State University,
Raleigh, NC).
Statistical analysis
Statistical calculations were performed using Prism
(GraphPad Software, Inc., San Diego, CA) and SAS
(SAS Institute, Inc., Cary, NC) software. To compare the
differences between a treatment group and the control group, a
t test was performed. ANOVA was used to test whether
differences between multiple groups were significant. If differences
were significant (P < 0.05), Tukey’s multiple
comparison test was then used for post-hoc evaluation of
differences between different treatment and control groups.
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Results |
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) and the expression levels (109 x
104 to 5512 x 104)
were within the range of those found for wild-type transgenic mice
[20 x 104 to 6000 x
104 RLU/mg protein from a previous study
(14A )]. These 5 founders were further analyzed for
luciferase expression in 7 other tissues (Table 1). Founders 7909 and
7913 showed high expression in the pituitary and only minor expression
in the brain and gonad, but no expression was observed in heart, lung,
liver, or spleen. Thus, the expression patterns of these 2 mutant
founders resembled that in wild-type founders (14A ).
However, 3 of the founder lines (3866, 7921, and 7910) expressed
luciferase in almost every tissue examined. As the lack of
pituitary-specific expression in these three founders could be a result
of transgene integration into an unusually permissive chromatin
environment, only founder lines 7909 and 7913 were analyzed further and
used for the GnRH/activin regulatory studies shown below.
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). Castration caused 2- and 7-fold
increases in transgene expression in male mice from both lines 7909 and
7913, respectively, compared with intact male mice. Levels of induction
in mut-oFSHßLuc expression after castration of males were similar to
those observed in male transgenic mice carrying wt-oFSHßLuc [2- to
8-fold from a previous study (14A )]. Castration of the
female mice caused 40- and 3-fold increases in transgene expression
from 7909 and 7913 lines, respectively, similar to the change in
transgene activity after castration in female transgenic mice carrying
wt-oFSHßLuc [2- to 27-fold from previous studies
(14A )]. These results indicated that two proximal AP-1
sites are not important for gonadal feedback regulation of the
transgene.
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). These data indicated that in mice
carrying AP-1 mutant oFSHßLuc, the transgene was regulated
appropriately by GnRH, strongly suggesting that the mut-oFSHßLuc
transgene is expressed in the gonadotropes like the wt-oFSHßLuc
transgene.
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). In
wt-oFSHßLuc transgenic mice, the difference in transgene activity
between estrus and diestrus ranges from 3- to 20-fold
(14A ). Therefore, the changes in oFSHßLuc activity
during the estrous cycle seen in transgenic mice were maintained even
when -83 and -120 AP-1 sites were mutated.
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). Two lines of mut-oFSHßLuc
transgenic mice (lines 7909 and 7913) were also injected with GnRH
antiserum, and the mutant transgene was repressed by 66% and 75%,
respectively, indicating that both the wt and mut transgenes are
regulated normally by GnRH.
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). These data suggested that these two
AP-1 sites are not involved in the regulation of FSHß gene expression
by follistatin.
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). Follistatin at 10 ng/ml
resulted in a maximal reduction of luciferase expression at 24 h.
A time course of the follistatin response was performed using the 250
ng/ml dose, and oFSHßLuc expression was decreased maximally at 8
h (Fig. 3B).
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). A time course of the activin
response was performed using a dose of 300 ng/ml. Control media or
media containing activin were added to follistatin-pretreated cultures,
and cells were harvested for determination of luciferase activity after
1, 2, 4, 6, 8, 16, and 24 h (Fig. 4B). In the absence of activin,
oFSHßLuc expression increased slowly over 24 h of treatment
(data not shown), indicating that factors were being made in the
culture to increase FSHß expression. In the presence of activin,
FSHßLuc expression was induced 6-fold at 2 h and a maximal
15-fold at 6 h (Fig. 4B). Thereafter, induction declined, and by
24 h, oFSHßLuc expression of the activin-treated cultures was
not significantly different from control levels. During activin
treatment, cells were incubated in media containing 1% serum to keep
basal expression low, because incubation with media containing 10%
serum often increased basal expression at a much faster rate, resulting
in reduced apparent induction by activin (data not shown).
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). A lower concentration of GnRH (0.1
nM) was not as effective, and the GnRH effect was decreased
at higher concentrations (
10 nM; Fig. 5A). At the highest
concentration of GnRH tested (100 nM), the GnRH
effect was completely abolished, suggesting that GnRH
down-regulation of FSHß synthesis began to occur at concentrations
higher than 1 nM. The GnRH dose-response experiment was
also performed with lower concentrations of activin (at 30 and 100
ng/ml), and the results were similar to those shown in Fig. 5A using
300 ng/ml activin (data not shown).
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). After 4 h of treatment, activin
and GnRH induced a maximal combined stimulation of 26-fold, with 9-fold
attributable to activin and an additional 2.9-fold due to GnRH.
Thereafter, the GnRH effect declined, and by 8 h, oFSHßLuc
expression in cultures treated with activin plus GnRH was not
significantly different from that in cultures treated with activin
alone.
Two proximal AP-1 sites are required for GnRH induction of FSHß
transcription in gonadotropes in culture
To evaluate the importance of the two proximal AP-1 sites
(-120/-83) for activin and GnRH responses in gonadotropes, pituitary
cultures from two lines of transgenic mice carrying the wild-type
transgene (7152 and 3861) or two lines of mice carrying the AP-1 mutant
transgene (7909 and 7913) were prepared. Cells were first treated with
follistatin for 16 h, and cells were washed. Media containing
activin alone, GnRH alone, or activin plus GnRH were then added to the
cultures, and cells were harvested 4 h after hormone addition. As
shown in Fig. 6A, transgene expression
from the 7152 wild-type cultures was increased 8.7-fold by activin, but
was not significantly increased by GnRH alone. Combined activin and
GnRH increased expression by 16.4-fold, with a significant additional
1.9-fold induction due to GnRH. Transgene expression from the 3861
wild-type cultures was increased 4.4-fold by activin, but was not
significantly increased by GnRH alone. However, activin plus GnRH
caused an 8.2-fold increase, with a significant additional 1.9-fold
induction from GnRH compared with activin alone (Fig. 6B).
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). GnRH alone had no effect on basal oFSHßLuc
expression. Combined treatment with activin and GnRH increased basal
expression, but only by 6.0-fold, lower than the fold induction
observed with activin alone. In the pituitary cultures derived from the
mutant 7913 line, activin increased basal expression 5.3-fold (Fig. 6D). GnRH alone again had no effect, and combined activin and GnRH was
not able to increase the expression of luciferase. These data indicate
that without AP-1 sites, oFSHß gene transcription can still be
regulated by activin, but the stimulatory effect of GnRH is completely
abolished. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been controversial whether activin increases FSHß gene expression by transcriptional regulation or by increasing the half-life of FSHß mRNA. Although activin has been shown to increase FSHß gene transcription by measuring nuclear FSHß primary transcripts (3), attempts to localize the activin response elements in the FSHß gene have been impeded by the lack of an FSH-producing cell line. Although the oFSHßLuc constructs can be expressed at high levels in many heterologous cell lines (13, 17, 18), no significant activin stimulation was observed in these transfected cells. It was not clear whether the activin response elements were outside the FSHß promoter used in these heterologous cells or if there was a defect in the activin signal transduction pathway that is normally present in gonadotropes to stimulate FSHß synthesis. Using pituitary cultures from the oFSHßLuc transgenic mice, activin was able to increase oFSHßLuc activity dramatically, indicating that activin, indeed, requires a gonadotrope environment to function properly. This activin response also strengthened the evidence showing that regulation of FSHß gene expression by activin can occur at the transcriptional level. Recently, LßT2, a gonadotrope-derived cell line, was shown to produce FSH in response to activin treatment (19), which may now serve as an appropriate in vitro model for rapidly mapping the activin response element(s) shown to be present in our ovine FSHßLuc constructs (19A ).
In transgenic mouse pituitary cultures, GnRH alone did not increase oFSHßLuc activity and required the presence of activin to obtain stimulation. The activin dependence of GnRH stimulation of FSHß gene expression has been reported when using a perifusion system (20) in which the constant medium flow removes endogenously secreted factors such as activin. As our pituitary cultures were pretreated with follistatin, it resembled the perifusion system, in that locally produced activin was removed by follistatin. It is unclear what mechanism(s) causes the GnRH response to be dependent on activin. One possibility is that activin stimulates the synthesis of GnRH receptors, which then sensitize gonadotropes to GnRH treatment. This hypothesis is supported by studies showing that activin increases gene transcription and protein synthesis of rat GnRH receptors (21, 22).
The time-course studies showed that stimulation of oFSHßLuc transgene activity by activin and/or GnRH in culture was evident at 2 h, reached a maximal induction at 4–6 h, and declined thereafter. The decline of stimulation may be due to desensitization of activin and GnRH receptors. Alternatively, as activin and GnRH have been shown to increase the production of follistatin in pituitary cells (20, 23), the induction of follistatin after treatment of activin and GnRH could block activin stimulation of the oFSHßLuc expression. By sequestering and neutralizing activin activity, stimulation of oFSHßLuc expression by GnRH could also be hindered, because GnRH requires activin to function as discussed above.
Stimulation of FSHß gene transcription by GnRH in vivo was reported to require pulsatile administration of GnRH, whereas continuous treatment for 4 h was not able to increase FSHß gene transcription using castrated male rats treated with testosterone to suppress endogenous GnRH release (9). The GnRH effect observed in our transgenic mouse pituitary cultures did not require pulsatile administration of GnRH. Consistent with our findings, another in vitro study showed that continuous GnRH treatment of perifused pituitary cells caused a 2.3-fold induction of FSHß mRNA levels at 4 h (20). This discrepancy between in vivo and in vitro data may be due to the different hormonal milieu surrounding pituitary cells in vivo compared with factors present in static or perifused pituitary cells.
Two proximal AP-1 sites (-83 and -120) in the oFSHß promoter were postulated to be important for GnRH regulation in vivo, because mutation of these AP-1 sites completely abolished GnRH induction of the oFSHßLuc expression in HeLa cells (14). The importance of these two AP-1 sites in GnRH stimulation of FSHß gene transcription in gonadotropes was confirmed in this current report. However, without these AP-1 sites, the mut transgene was still repressed by anti-GnRH or chronic GnRH agonist (Lupron) treatment as if it were the wt transgene, suggesting that the two AP-1 sites are not required for GnRH to stimulate FSHß gene expression in vivo. The effects of anti-GnRH or Lupron are probably not due to a direct change in the basal transcription rate of the FSHß gene, but, instead, to a more global change in gonadotropes, eventually leading to a decrease in transgene expression. Data that support this hypothesis include studies showing a slower decline in the plasma FSH level (19% after 2 h) after administration of GnRH antibody compared to that in the plasma LH level (85% after 2 h) (24). In conclusion, these AP-1 sites are not responsible for any of the GnRH effects investigated in vivo in this report, and the importance of these AP-1 sites may involve some GnRH-stimulated effect not yet defined.
In the absence of two proximal AP-1 sites, basal expression levels of the transgene were comparable to those observed with the wild-type transgene in 5 of 10 founders, suggesting that these AP-1 sites may not be important for FSHß gene expression in the pituitary. The specificity of tissue expression of the transgene, however, was somewhat decreased in mice that carry the mut transgene, with 3 of 5 founder lines expressing significant transgene activity in tissues other than the pituitary. It is possible that these 2 AP-1 sites are important sequences that restrict FSHß expression to the pituitary. However, 2 mut-oFSHßLuc transgenic lines (7909 and 7913) still expressed luciferase primarily in the pituitary as with wt-oFSHßLuc. It should also be noted that, as shown in the companion paper (14A ), 1 of 6 founders that carry the wt-oFSHßLuc transgene also expressed luciferase in many tissues as well as the pituitary, suggesting that expression in tissues outside the pituitary could be a result of transgene integration into an unusually permissive chromatin environment. More lines will need to be generated to clarify the roles of these two AP-1 sites in tissue-specific expression.
In summary, transgenic mice were generated that carry the mut-oFSHßLuc gene with -120 and -83 bp AP-1 sites destroyed. The mutant transgene was expressed in pituitary gonadotropes and was regulated in the same way as the wild-type transgene, suggesting that these AP-1 sites are not important for the tissue-specific expression and hormonal regulation involved with castration, Lupron treatment, GnRH withdrawal, and/or cyclic changes in vivo. Using the pituitary cultures derived from wt-oFSHßLuc transgenic mice, activin and GnRH stimulation of the oFSHß gene transcription in gonadotropes was demonstrated. The observed activin response showed, for the first time, that the ovine FSHß promoter (-4741 to +759 bp) is responsive to activin, which suggests that the DNA sequences responsible for activin action may be mapped using the FSH-producing gonadotrope cell line, LßT2. Moreover, by comparing the in vitro responses to GnRH in wt- and mut-oFSHßLuc transgenic mice, it is apparent that the AP-1 sequences at -120/-83 bp are important for GnRH-mediated induction of oFSHß gene expression in gonadotropes.
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Acknowledgments |
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Footnotes |
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2 Present address: LabCorp, Research Triangle Park, North Carolina
27709.
3 Present address: Department of Medicine-Biochemistry, University
of Virginia, Charlottesville, Virginia 22906.
Received September 11, 2000.
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References |
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, ßA,
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H.-J. Huang, J. Sebastian, B. D. Strahl, J. C. Wu, and W. L. Miller The Promoter for the Ovine Follicle-Stimulating Hormone-{beta} Gene (FSH{beta}) Confers FSH{beta}-Like Expression on Luciferase in Transgenic Mice: Regulatory Studies in Vivo and in Vitro Endocrinology, June 1, 2001; 142(6): 2260 - 2266. [Abstract] [Full Text] [PDF]
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H.-J. Huang, J. C. Wu, P. Su, O. Zhirnov, and W. L. Miller A Novel Role for Bone Morphogenetic Proteins in the Synthesis of Follicle-Stimulating Hormone Endocrinology, June 1, 2001; 142(6): 2275 - 2283. [Abstract] [Full Text] [PDF]
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