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Department of Pathology (K.H.B., C.Y., T.R.K., M.M.M.), Department of Molecular and Human Genetics (K.H.B., M.M.M.), and Department of Molecular and Cellular Biology (T.R.K., M.M.M.), Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D., Professor and Stuart A. Wallace Chair, Department of Pathology, One Baylor Plaza, Baylor College of Medicine, Houston Texas 77030.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylase and LH receptor messenger RNAs (mRNAs). This
indicates that theca recruitment is completed autonomously with respect
to FSH. 2) Granulosa cells in FSH-deficient mice demonstrate an
increase in FSH receptor mRNA, and decreases in P450 aromatase,
serum/glucocorticoid-induced kinase, and inhibin/activin subunit
mRNAs. These data support studies that implicate FSH signaling cascades
in the expression of these genes. 3) In contrast to the thecal layer,
granulosa cell populations in FSHß knockout mice do not accumulate LH
receptor mRNA. This suggests that although the granulosa cells have a
block in proliferation at the antral follicle stage in the absence of
FSH, they do not initiate programs of terminal differentiation as seen
in luteinizing cells of wild-type ovaries. 4) Ovaries of FSH-deficient
mice demonstrate a modest decrease in cyclin D2 mRNA, without
up-regulation of cell cycle inhibitor mRNAs associated with
luteinization (i.e. p15, p27, and p21). Although
components of the FSH null phenotype may be caused by partial cyclin D2
loss of function, these findings indicate that the mechanisms of
granulosa cell cycle arrest in FSHß knockout mice are distinct from
those of cycle withdrawal at luteinization. Underscoring the usefulness
of the FSH-deficient mouse model, this study clarifies aspects of
gonadotropin-dependent folliculogenesis, thecal layer development,
cycle control in granulosa cells, and luteinization. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit and a unique ß-subunit. FSH
and LH are synthesized in gonadotroph cells of the anterior pituitary
and act on their cognate receptors in the gonads (1). FSH
receptors (FSHRs) are transmembrane proteins present in the female on
granulosa cells of growing follicles. LH receptor (LHR) expression is
limited to the surrounding theca cells in preantral follicles, and as
development proceeds, granulosa cells of preovulatory follicles and
corpora lutea also express LHRs (2). Recruitment of primordial follicles and the first phases of follicle development can proceed independently of the gonadotropins, although FSHR messenger RNA (mRNA) is expressed as early as the primary follicle stage (3). FSH plays an essential role in the later progression of folliculogenesis. In maturing follicles, FSH mediates continued mitotic activity of granulosa cells, and decreased FSH responsiveness is associated with follicular atresia (4). There is a complex interplay between developing follicles and the pituitary. FSH elicits granulosa cell peptide and steroid hormone production by inducing the expression of inhibin/activin subunits and steroidogenic enzymes (4). Inhibins and activins are dimeric peptide hormones of the transforming growth factor-ß (TGFß) superfamily and are named for their functions in attenuating and enhancing pituitary FSH production, respectively. The midcycle LH surge is also coordinated in part by ovarian endocrine factors (1). Ovulation and luteinization of dominant follicles in response to LH depend on LHR expression that is also up-regulated by FSH (4).
We previously demonstrated that female mice homozygous for a disruption at the hormone-specific FSHß locus, and therefore deficient in FSH, are infertile due to a block in folliculogenesis (5). Ovaries of these mice accumulate multilayered preantral follicles, which fail to develop antra and consequently do not ovulate. Interestingly, FSH-deficient male mice retain fertility, although they exhibit decreased testicular weight and low epididymal sperm counts (5). As expected, the ovarian phenotype in FSHR knockout mice is similar to what is observed in the FSH ligand knockout mice (6). FSHR-deficient female mice are also infertile due to a block in folliculogenesis preceding antral development.
These findings in mice phenocopy human mutations in FSHß (missense and frameshift/truncation) and FSHR (missense) (7). Women who are homozygous or compound heterozygous for these ligand or receptor mutations are infertile. The structural conservation of FSHß and FSHR proteins (8, 9) across mammalian species and the functional rescue of FSHß knockout mice with a human FSHß transgene (10) also demonstrate the relevance of mouse models for studies of human infertility. To better describe FSH deficiency syndromes and define the genetic targets of FSH, we analyzed the expression of specific mRNAs in ovaries of FSH null mice by Northern blot analysis and in situ hybridization. The findings enhance our understanding of key molecular events of late folliculogenesis, granulosa cell proliferation, and luteinization.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Northern blot analysis
Total RNA was isolated from pooled ovaries of 8–16 mice by acid
guanidinium thiocyanate-phenol-chloroform extraction using the RNA
STAT-60 reagent (Leedo Medical Laboratories, Houston, TX). Fifteen
micrograms of each RNA sample were used for electrophoresis and
transfer onto nylon membranes as described previously
(11). Radioactive complementary DNA (cDNA) probes were
synthesized from the templates listed in Table 1
using
[32P]dATP and the Strip-EZ kit
(Ambion, Inc., Austin, TX). Autoradiography and
phosphorimaging allowed for visualization and quantification of probe
hybridization, respectively. Phosphorimaging plates were scanned and
analyzed using ImageQuant software (Molecular Dynamics, Inc., Sunnyvale, CA) (12). A background level for
each blot was determined and subtracted. Blots were stripped and
reprobed for glyceraldehyde 3-phosphate dehydrogenase (GAPDH),
and phosphorimaging of the GAPDH signal allowed us to correct
each lane for RNA loading.
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-35S]uridine triphosphate-labeled antisense
and sense riboprobes were transcribed from the corresponding cDNA
sequences listed in Table 1
using T7, T3, or SP6 polymerases
(Promega Corp., Madison, WI). Paraffin-embedded ovaries
were cut into 5- to 7-µm sections, dewaxed, fixed, hybridized, and
washed as detailed (14). Signal was detected by
autoradiography using NTB-2 emulsion (Eastman Kodak Co.,
Rochester, NY). Hematoxylin counterstaining allowed ready correlation
of the hybridization to specific cell populations within the ovary. |
Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
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); LHR mRNA in the null sample is 5-fold less than the
quantity detected in the wild type. In wild-type mice, LHR is expressed
in corpora lutea (Fig. 2, A and B),
preovulatory granulosa cells (not shown), and, to a lesser degree,
theca and interstitial cells (not shown). In situ
hybridization experiments indicate the main sources of expression in
the FSHß knockout mice are theca (Fig. 2, C and D) and interstitial
cell populations. The interstitial cell expression is particularly
noticeable in the occasional cyst of an FSH-deficient mouse ovary,
where the interstitial cells surround the fluid-filled space (Fig. 2, E
and F).
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Steroidogenic enzymes
FSH has been implicated in the control of enzymes critical to
steroid hormone generation in the ovary, namely the mitochondrial
cholesterol side chain cleavage protein (P450scc or CYP11A) and P450
aromatase (CYP19) (4, 17, 18). Conversely, steroids
feedback to affect FSH production and act within a developing follicle
to modulate the FSH response.
The conversion of cholesterol to the 21-carbon progestins, pregnenolone
and progesterone, requires P450scc (CYP11A). Using in situ
hybridization and immunochemistry, we previously showed that P450scc
enzyme mRNA is expressed in murine corpora lutea, theca cells, and
interstitial cells (13). Northern blot analysis
demonstrates a more than 6-fold decrease in P450scc mRNA levels in
ovaries of FSH-deficient mice compared with those of wild-type controls
and Fshb heterozygote littermates (Fig. 3A). This result is likely due to a lack
of histological and functional corpora lutea in the FSHß knockout and
neither substantiates nor refutes a direct role for FSH in the
regulation of P450scc expression.
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-hydroxylase
activity (17OH; P45017; CYP17) in the thecal layer, and 17OH
expression can be used as a marker for assessing theca recruitment
(13). Abundance of the 17OH enzyme mRNA increases
2-fold in ovaries of Fshb-/- mice
compared with wild-type controls, perhaps reflecting a response to the
increased circulating LH in these mice (Fig. 3B) (5).
In situ hybridization analysis of 17OH expression
confirms that multilayered follicles of the FSH null mice are
surrounded by a well defined thecal layer; there is also an abundance
of interstitial cells that express 17OH in these ovaries (Fig. 3, F
and G). As expected, the wild-type ovaries demonstrate expression of
17OH in the theca cells surrounding preantral and antral follicles
and also in the interstitial cells (although these are less abundant
than in the FSHß knockout ovary) (Fig. 3, D and E).
Cytochrome P450 aromatase (CYP19) is expressed in granulosa cells of
preovulatory follicles, allowing these cells to produce estrogens from
androgens made in the surrounding theca compartment. Ovaries of FSHß
knockout mice have markedly decreased quantities of aromatase mRNA
(>6-fold) compared with controls (Fig. 3C).
TGFß superfamily members and follistatin
Inhibins (:ßA and :ßB) and activins (ßA:ßA,
ßB:ßB, and ßA:ßB) are assembled from subunits that are
expressed in overlapping patterns in granulosa cells of growing
follicles. Although FSH is a key positive regulator of inhibin
(Inha) mRNA (19), immunodetectable -subunit
has been located in the earliest follicles (20), and
absence of FSH does not abrogate its expression. Only a modest
reduction (50%) in Inha mRNA is observed by Northern blot analysis in
the FSH-deficient mouse ovary compared with wild-type ovaries (Fig. 4A). Inha is most prominently expressed
in granulosa cells of multilayered through preovulatory wild-type mouse
follicles (13) (Fig. 5, A
and B); in situ hybridization demonstrates expression of
Inha mRNA in the multilayered preantral follicles of the
Fshb-/- mice (Fig. 5, C and D).
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, B and C).
Thus, although the -subunit is expressed, no inhibin (:ß)
heterodimers are expected to be produced, and therefore no functional
gonadal feedback loop to the pituitary is expected in these mice.
Follistatin is an antagonist of activin function in the pituitary and
ovary by virtue of its binding to the ß-subunit
(21, 22, 23). Follistatin is expressed in granulosa cells
(24) and can be induced in vitro by FSH
(25). Interestingly, absence of FSH and reduced activin
levels in the FSHß knockout mice slightly decrease, but do not
abrogate, the expression of follistatin (Fig. 4D).
Cell cycle progression
In dominant follicles, FSH promotes granulosa cell proliferation,
and it is reasonable to view the folliculogenesis arrest in
Fshb-/- mice as, in part, a failure
of these cells to divide. To describe cell cycle aberrations in the
ovaries of these mice, we examined expression of genes implicated in
the granulosa G1
S phase transition.
Cyclin proteins advance cell cycle progression and promote cell
proliferation. Cyclin D2 (Ccnd2) has been shown specifically
to be essential for granulosa proliferation in multilayered follicles
(26). Cyclin D2 mRNA is induced by FSH (26)
and is down-regulated by LH (27). Interestingly,
quantities of cyclin D2 mRNA are only modestly decreased in the absence
of FSH in vivo. Granulosa cells in
Fshb- /- mice maintain 70% of
wild-type cyclin D2 expression levels (Fig. 6A and Fig. 7). Thus, FSH signaling is not required
for the expression of this important cyclin in the mammalian ovary.
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, B and C).
Countering effects of the cyclin/cdk complexes are cell cycle inhibitor
proteins. Two such inhibitors, p27Kip1 and
p21Cip1, are expressed by granulosa cells in
response to LH, and both mRNAs are maintained at high levels in corpora
lutea (27). Ovaries of
Fshb-/- mice demonstrate 3-fold and
5-fold reductions in p27Kip1 and
p21Cip1 mRNAs, respectively, compared with
controls (Fig. 6, D and E and Fig. 8). Another cell cycle
inhibitor, p15Ink4b, is markedly down-regulated
(>10 fold) in the ovaries of
Fshb-/- mice (Fig. 6F). In
situ hybridization localizes p15Ink4b
expression to corpora lutea in the wild-type ovary (Fig. 9, A and B), thereby making
p15Ink4b another cell cycle inhibitor associated
with luteinization and granulosa cell withdrawal from the cell cycle.
Taken together, these results indicate that the arrest of granulosa
cell proliferation in the absence of FSH is controlled by cellular
mechanisms quite distinct from those that normally regulate granulosa
cell terminal differentiation at the time of luteinization.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), and
distributions of mRNA species within the ovary were characterized by
in situ hybridization analyses.
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In Fshb-/- mice, follicular development appears to progress normally to the multilayered preantral stage, at which point FSH signaling becomes critical (5). FSH responsiveness is essential at this point in follicular development, and factors that down- regulate FSHR also prompt follicular atresia (4). Consistent with their preparedness to respond to exogenously administered gonadotropins (5), we find granulosa cells of FSH-deficient mice up-regulate expression of FSHR. There is no appreciable ligand-independent receptor activity in Fshb-/- mice as evidenced by the close resemblance of FSHß and FSHR knockout folliculogenesis defects (5, 6). Interestingly, genetic models have indicated that FSH signaling is quite sensitive to the quantity of functional FSHR. FSHR heterozygous females, although fertile, show partial expressivity of the FSH-deficient phenotype (6). Moreover, insulin-like growth factor I (IGF-I) knockout females have attenuated expression of FSHR and demonstrate a preantral folliculogenesis block, likely caused by inadequate FSH signaling (29, 30).
Granulosa cells respond to FSH in part by elaborating peptide
autocrine/paracrine/endocrine factors, such as inhibins and activins
(21). We find that accumulation of the -inhibin subunit
mRNA is only partially compromised in the
Fshb-/- mouse ovary, while
transcripts of inhibin/activin ßA and ßB subunits are virtually
undetectable. Thus, though ovarian -inhibin expression is present in
FSHß and FSHR knockout mice, our results suggest that FSH signaling
may be essential to ß-subunit expression in vivo and the
production of functional inhibin (:ß) and activin (ß:ß)
dimers. Despite the differential expression of inhibin/activin
subunits, expression of the activin antagonist follistatin is
essentially unchanged in the ovaries of FSH null mice. Follistatin also
binds other members of the TGFß superfamily, and the presence of
follistatin mRNA in the FSHß knockout suggests it may regulate
effects of other TGFß signaling proteins such as those produced in
the oocyte [e.g. growth differentiation factor 9 (GDF-9)
and bone morphogenetic protein 15 (BMP-15)] or theca cells
(e.g. BMP-2 and BMP-7).
FSH regulates ovarian steroid production by inducing the expression of steroidogenic enzymes (4, 31). Expression of P450 aromatase and P450 side chain cleavage (P450scc) enzymes is contingent on FSH signaling in developing follicles, while luteinization initiates their constituitive expression (17, 18). Ovaries of Fshb-/- mice exhibit a striking down-regulation of P450 aromatase and P450scc mRNAs. Findings of normal serum estrogen in FSHß knockout females (5) and estrous periodicity in FSHR knockouts (6) perhaps indicate that a nonovarian compensatory mechanism can function to maintain steroid hormone production. It remains to be established whether local concentrations of steroids are altered in the ovaries of Fshb-/- mice, an intriguing question because of the intrafollicular functions of steroids. The convergence of gonadotropin and steroid pathways in regulating gene expression, as is the case for cyclin D2, adds complexity to the delineation of FSH and estrogen functions (32).
Androgen and estrogen biosynthesis depend on the LH-mediated expression
of theca cell 17OH (P45017; CYP17), and 17OH mRNA is a marker
of theca morphology (13). In situ hybridization
to 17OH mRNA in ovaries of
Fshb-/- mice reveals a well formed
thecal layer circumscribing each follicle, confirming our early
observations that theca recruitment can proceed independently of FSH
signaling (5). The elevated expression levels,
particularly noticeable in the interstitial cell population by in
situ hybridization, may reflect an effect of high serum LH in
these mice (5). Interestingly, establishing that theca
formation is independent of FSH signaling has implications for models
that involve IGF-I in the process. Ovarian failure in IGF-I-deficient
mice has been ascribed to loss of FSH signaling function, although the
phenotype includes an underdevelopment of normal structural features of
the theca cells. Given our data, theca cell dysfunction in ovaries
lacking IGF-I would be caused by a mechanism distinct from the loss of
FSH signaling (29, 33, 34, 35).
A paradigm for granulosa differentiation has emerged whereby proliferating cells of preovulatory follicles become responsive to LH and are then competent to be programmed for terminal differentiation and luteinization. Granulosa cells within arrested follicles in Fshb-/- mice do not express detectable LHR and, as a result, may lack potential for LH-mediated steps toward terminal differentiation. Interestingly, this is in contrast to other transgenic models of abnormal folliculogenesis, including the GDF-9 and cyclin D2 knockout mice, which both exhibit elements of appropriate LH responsiveness (13, 36). To characterize the unique granulosa cell suspension in FSHß knockout mice, we quantified transcripts of cyclin D2, Cdks (Cdk2 and Cdk4), and Cdk inhibitors (p27Kip1 and p21Cip1), which are implicated in controlling proliferation and luteinization of these cells (28, 36). FSH is believed to promote cell division in part by prompting the transcription of cyclin D2 mRNA (26). Consistent with this premise, the failure of granulosa cells to divide in our mouse model is reminiscent of the phenotype of mice with targeted inactivation of the cyclin D2 locus. Cyclin D2 knockout females are infertile, and granulosa cells do not proliferate to form more than four or five concentric layers in developing follicles (26). Despite large numbers of granulosa cells in the Fshb-/- mouse ovary, we have shown that there is a modest decrease in total cyclin D2 mRNA. It also appears to us that a down-regulation of cyclin D2 mRNA is detectable by RT-PCR analysis of FSHR-/- mice (6). This is consistent with models that place cyclin D2 downstream of FSH, although the hormone is clearly not prerequisite for cyclin D2 expression in granulosa cells. It is possible that reduced cyclin D2 activity in the absence of FSH is important and sufficient mechanistically for creating the granulosa cell cycle arrest.
LH induces expression of p27Kip1 and p21Cip1 in granulosa cells while down-regulating cyclin D2 (27). This shift to favor antiproliferative intracellular factors accompanies the terminal differentiation of luteinizing cells (27, 36). Indeed, p27-deficient females exhibit granulosa cell hyperplasia and a failure of luteinizing cells to withdraw from the cell cycle and produce factors necessary to support implantation and early pregnancy (37). We now document decreases in p27Kip1 and p21Cip1 expression in the FSH-deficient mouse ovary, presumably reflecting the lack of granulosa cell LH signaling. These data indicate that the cell cycle block arresting folliculogenesis in the FSHß null mice is not dependent on the up-regulation of Cdk inhibitors associated with cell cycle withdrawal at luteinization.
Complex events underlie the pleiotropic effects of FSH in the mammalian ovary, and the FSH-deficient mouse model has enabled us to more precisely address questions pertaining to the hormone’s necessity. Information from these efforts will further investigations of the mechanisms of gene expression, as well as cellular differentiation and proliferation, in hormonally responsive tissues.
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Acknowledgments |
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Footnotes |
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2 Student in the Medical Scientist Training Program supported, in
part, by NIH Grant T32GM-07330 and Grant T32EY07102 from The National
Eye Institute.
Received February 6, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and ß-subunit
complementary deoxyribonucleic acids and expression in the ovary. Mol
Endocrinol 1:561–568[CrossRef][Medline]
-, ßA-, and ßB-subunits in ovarian cell types during the
rat estrous cycle. Mol Endocrinol 2:1352–1363[CrossRef][Medline]
luteal transition. Cell Growth Differ 9:787–794[Abstract]
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