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Children’s Hospital (M.H.), University of Helsinki, 00290 Helsinki, Finland; Departments of Pediatrics (M.H., M.E., M.B., N.N., D.B.W.) and Molecular Biology and Pharmacology (D.B.W.), Washington University, St. Louis, Missouri 63110; Department of Obstetrics and Gynecology (J.S.T.), University of Oulu, 90220 Oulu, Finland; Department of Physiology (N.A.R., I.T.H.), University of Turku, 20520 Turku, Finland
Address all correspondence and requests for reprints to: Dr. David B. Wilson, Department of Pediatrics, Box 8116, Washington University School of Medicine, St. Louis Children’s Hospital, 1 Children’s Place, St. Louis, Missouri 63110. E-mail:wilson_d{at}kidsa1.wustl.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although significant advances have been made in our understanding of ovarian development and function, the transcription factors that determine lineage commitment and cell proliferation in the ovary are not fully understood (10). Among the transcription factors that have recently emerged as potential regulators of gonadal gene expression and function are the GATA-binding proteins, a family of structurally related zinc finger proteins that recognize the consensus sequence (A/T)GATA(A/G), known as the "GATA" motif, which is an essential cis-element in the promoters or enhancers of a variety of genes (11). In Drosophila, a GATA-binding protein known as dGATAb is expressed in ovarian follicular cells, where it binds and activates the yolk protein genes Yp1 and Yp2 (12). In vertebrates, six GATA-binding proteins, termed GATA-1, -2, -3, -4, -5, and -6, have been described (11, 13). The DNA-binding specificities of different members of the vertebrate GATA-binding protein family are largely indistinguishable (14, 15), but these transcription factors exhibit different spatial and temporal expression patterns and are therefore presumed to serve different functions in the organism. Through targeted mutagenesis, several of these vertebrate factors have been shown to be critical regulators of differentiation (16, 17, 18, 19, 20). For example, GATA-1, -2, and -3, which are expressed in bone marrow cells, are required for normal hematopoiesis (16, 17, 18, 20). Moreover, a reduction in GATA-1 expression or activity has been associated with increased apoptosis in erythroid cells (21, 22, 23). Northern analysis and RT-PCR assays have shown that two vertebrate GATA-binding proteins, GATA-4 and GATA-6, are expressed in adult ovarian tissue and a limited number of other tissues, including heart, gut epithelium, and yolk sac endoderm (13, 19, 24, 25, 26, 27, 28, 29, 30, 31). The cell types within the ovary that express these transcription factors have not been elucidated. Given the established role of GATA-binding proteins in the regulation of gene expression, differentiation, and apoptosis in different cell types, it is intriguing to consider the possibility that transcription factors GATA-4 and GATA-6 participate in the development and/or function of the mammalian ovary. Additional support for the notion that GATA-binding proteins are involved in gonadal development comes from studies of GATA-1, which has been shown to be expressed in a developmental- and stage-specific manner in Sertoli cells of the testes (32, 33).
To gain insight into the role(s) of GATA-4 and GATA-6 in ovarian cell differentiation and function, we have examined the expression of these factors in the mouse ovary during fetal and postnatal development, using in situ hybridization. Furthermore, we have determined the temporal and spatial expression of GATA-4 and GATA-6 transcripts in immature mice treated with hormones to induce synchronized follicular development and ovulation. Herein we demonstrate that GATA-4 and GATA-6 have distinct patterns of expression during development and in response to hormonal stimulation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In situ hybridization
Mouse embryos or dissected tissue were washed briefly in PBS and
then frozen in OCT cryopreservation solution (TissueTek, Miles, Inc.,
Elkhart, IN). Frozen sections (10 µm) were fixed in 4%
paraformaldehyde in PBS and subjected to in situ
hybridization as described (35). Tissue sections were incubated with
1 x 106 cpm of [33P]-labeled antisense
or sense riboprobe in a total volume of 80 µl. Antisense and sense
riboprobes against the 5' end of mouse GATA-4 were prepared as
described elsewhere (24, 31). To generate antisense riboprobes for
GATA-6, a plasmid containing a partial length complementary DNA (cDNA)
encoding mouse GATA-6 (30) was linearized with either EcoRV
or PstI and transcribed in vitro with Sp6
polymerase in the presence of [33P]UTP (1000–3000
Ci/mmol, Amersham Life Sciences, Arlington Heights, IL);
EcoRV digestion yielded a 610 nucleotide probe that
recognized the distal zinc finger domain and 3'-end of the GATA-6
coding region, whereas PstI produced a 140-nucleotide probe
that recognized only the 3'-end of the GATA-6 coding sequence. These
two probes yielded identical results with in situ
hybridization. Sense riboprobe for GATA-6 was generated with T7
polymerase after linearization with BamHI.
Primary cultures of mouse granulosa cells
Mouse granulosa cells were obtained by follicular puncture using
a fine needle as described (36) from 3-week-old immature mice primed
with diethylstilbesterol (DES) 12 µg/day ip for 5 days. The cells
were cultured on plastic dishes in DMEM supplemented with 10% FCS,
L-glutamine (2 mM) and penicillin (100 U/ml),
streptomycin (100 µg/ml), and used for immunohistochemistry after
2–3 days in culture.
Immunohistochemistry
Cultured granulosa cells were fixed with 4% paraformaldehyde
and subjected to immunohistochemistry using either affinity purified
rabbit antimouse GATA-4 IgG (1 µg/ml) (24, 31) or nonimmune IgG as
the primary antibody. A commercially available avidin-biotin
immunoperoxidase system was employed to visualize bound antibody
(Vectastain Elite ABC Kit). 3,3'-diaminobenzidine tetrahydrochloride
dihydrate (Sigma Chemical Co., St. Louis, MO) was used as the chromogen
and the development reaction occurred in the presence of 0.01%
H2O2 and 0.03% NiCl2 (37).
Hormonal stimulation of immature mice
Immature female mice, aged 19–21 days, were primed with a
single ip injection of 5 U PMSG. Some of these animals were injected
with 5 IU human CG (hCG) 48 h later. Mice were killed 48 h
after PMSG or 5 h, 16 h, or 5 days after hCG injection to
obtain ovaries containing preovulatory, postovulatory, and luteinized
follicles (38). In the postovulatory group, ovulation was documented by
microscopic demonstration of oocytes in the oviduct. Control animals of
the same age did not receive any hormone injections. Each treatment
group consisted of 6–9 mice.
Alternatively, immature mice (19–23 days) were treated with steroid hormones, using a modification of a procedure developed for rats (7). Stocks of DES or testosterone were prepared by suspending the steroids at a concentration of 2.5 mg/ml in 95% mineral oil and 5% ethanol. Groups of mice were initially primed by twice daily 0.1 ml ip injections of DES. Two days later, the mice were divided into one of three treatment groups: the first group continued to receive twice daily injections of DES (i.e. continued estrogen stimulation), the second group received no further treatment (i.e. estrogen withdrawal), and the third group received twice daily 0.1 ml injections of testosterone (i.e. estrogen withdrawal plus testosterone treatment). Two days later, the ovaries were harvested and cryosectioned for in situ hybridization and apoptosis.
Gonadotropin stimulation of tumor cell lines
MSC-1 Sertoli tumor cells, derived from a transgenic mouse line
bearing a human Müllerian inhibiting substance promoter-SV40
T-antigen transgene (39), were obtained from Dr. M. Griswold
(University of Washington, Seattle, WA). MSC-1 cells were stably
transfected with a cDNA encoding the rat FSH receptor (FSHR) (Eskola,
V., M. Savisalo, A. Rannikko, K. Kananen, R. Sprengel, and I.
Huhtaniemi, unpublished studies). The resultant cells, termed
MSC-1/FSHR, cells were stimulated with recombinant FSH 50 IU/liter for
varying lengths of time. The NT-1 granulosa tumor cell line (passage
no. 4) was derived from transgenic mice bearing an inhibin
subunit
promoter-SV40 T-antigen contruct (40). The cells were stimulated with
recombinant FSH (50 IU/liter), hCG (50 µg/liter), or forskolin (10
µM) for the indicated lengths of time. Total RNA was
isolated using guanidinium thiocyanate-phenol-chloroform extraction and
analyzed for expression of GATA-4 or GATA-6 message using Northern
hybridization (24). Twenty micrograms of denatured total RNA was
subjected to electrophoresis on a 1% denaturing agarose gel and then
transferred onto nylon membranes (Hybond N, Amersham). The membranes
were hybridized with [32P]labeled cDNA probes for GATA-4
(24) or GATA-6 (27). Hybridization and washing of the membranes were
performed as previously described (24). Hybridization signals were
detected by autoradiography using Kodak X-Omat AR Diagnostic film XAR5.
Autoradiograms were scanned by the Microcomputer Imaging device (MCID,
version 1.2, from Imaging Research, Inc., St. Catherines, Ontario,
Canada) to quantify messenger RNA (mRNA) species.
In situ apoptosis
Parallel sections of ovaries used for in
situ hybridization were subjected to in situ analysis
for apoptosis, using nonisotopic 3'-labeling of DNA in the presence of
terminal transferase and digoxigenin-labeled ddUTP (ApopTag Kit, Oncor
Inc., Gaithersburg, MD). Labeled DNA was detected by fluorescence
conjugated antidigoxigenin antibodies, according to the manufacturer’s
directions. Sections were lightly counterstained with propidium iodide
and photographed using an Olympus fluorescent microscope.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In initial studies, we surveyed fetal mouse tissue sections for
expression of GATA-4 or GATA-6 mRNA. Although large amounts of message
for GATA-4 and GATA-6 can be detected in heart and intestinal
epithelium during fetal development (24, 29, 30, 31), only small amounts of
these two transcripts were detected in the fetal ovary between 15 and
18 days p.c. (data not shown). Ovarian expression of GATA-4
mRNA increased around the time of birth (Fig. 1
, A and
B). Expression of GATA-4 by granulosa cells persisted through
subsequent stages of development (see below). The onset of GATA-6 mRNA
expression in the developing ovary was delayed compared with GATA-4;
little GATA-6 message was evident in the ovaries of newborn animals
(Fig. 1, C and D), and only trace amounts of GATA-6 mRNA were
detectable in granulosa cells of the three week old juvenile ovary (see
below).
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, C and D). Moderate amounts of GATA-4 expression were
also observed in theca cells, the germinal epithelium, and interstitial
cells of adult ovaries (Fig. 2, C and D). Expression of GATA-4 mRNA in
the theca cell layer was best appreciated under bright field optics, as
shown in Fig. 3A. Little or no GATA-4 mRNA expression
was seen in oocytes, oviduct, or uterus. As was the case with GATA-4,
large amounts of GATA-6 mRNA were evident in granulosa cells of adult
animals (Fig. 2, E and F). Moderate levels of GATA-6 message were also
detected in the germinal epithelium (Fig. 2E), but no GATA-6 message
was evident in theca cells, interstitial cells, or oocytes (Figs. 2, E
and F, and 3B). Whereas little GATA-4 mRNA expression was evident in
the corpus luteum of adult animals (Fig. 2D), abundant GATA-6
expression was detected in luteal tissue (Fig. 2F). Faint expression of
GATA-6 but not GATA-4 message was seen in the proximal oviduct (Fig. 2, C and E). Thus, GATA-4 and GATA-6 display differing patterns of
expression in the mouse ovary.
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), consistent with
earlier studies showing that GATA-4 localizes to the nucleus in
cardiomyocytes (42, 43) and differentiated F9 embryonal carcinoma cells
(41). Control staining of cultured granulosa cells with nonimmune IgG
yielded only weak, nonspecific, cytoplasmic staining (Fig. 4B). Thus,
both GATA-4 message and protein are present in mouse granulosa cells.
Because an antibody directed against GATA-6 was not available, we did
not directly assess whether GATA-6 protein is present in granulosa cell
cultures.
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and 6, respectively. In unstimulated 3-week-old ovaries,
GATA-4 mRNA was evident in granulosa cells of primary and preantral
follicles (Fig. 5A), whereas little or no GATA-6 expression was present
in these early follicles (Fig. 5B). Robust expression of both GATA-4
and GATA-6 mRNA was seen in the granulosa cells of antral follicles
48 h after PMSG injection (Fig. 5, C and D). Message for GATA-4,
but not GATA-6, was also evident in theca cells 48 h after PMSG
injection. Administration of hCG to PMSG-primed immature mice resulted
in an abrupt decrease in GATA-4 message in granulosa cells of
preovulatory follicles, whereas GATA-4 mRNA expression persisted in
theca cells (Figs. 5E and 6A). Within preovulatory follicles present at
5 h post hCG administration, cumulus granulosa cells (immediately
adjacent to the oocyte) expressed more GATA-4 mRNA than granulosa cells
near the follicular basement membrane (Fig. 5E). This finding is
consistent with previous studies demonstrating that, at later stages of
development, cumulus granulosa cells express different markers and
function differently than mural granulosa cells (10). After ovulation,
granulosa cells expressed little or no GATA-4 mRNA. When hCG was
administered to PMSG-primed immature mice, we observed GATA-6 message
in granulosa cells both before and after ovulation (Figs. 5F and 6B).
In contrast to GATA-4 mRNA, GATA-6 message in preovulatory follicles
was more abundant in mural granulosa cells near the basement membrane
than in cumulus granulosa cells. No GATA-6 expression was detected in
theca cells in response to hormonal stimulation. Corpora lutea that
appeared 5 days after stimulation of PMSG-primed juvenile ovaries with
hCG were essentially devoid of GATA-4 message (Figs. 5G and 6C) but
expressed significant amounts of GATA-6 (Figs. 5H and 6D). The low
magnification views in Fig. 6 emphasize that the hormone-induced
changes in expression of GATA-4/6 are uniform.
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). FSH stimulation of MSC-1/FSHR cells resulted in an
increase in the expression of GATA-4 message, whereas GATA-6 mRNA
expression was not affected by FSH treatment. Next, we examined NT-1
cells, a granulosa tumor cell line that exhibits properties of normal
granulosa cells, including expression of endogenous gonadotropin
receptors, steroidogenic enzymes, and inhibin (40). We stimulated
low passage NT-1 cells with FSH, hCG, or forskolin and measured
GATA-4/-6 expression by Northern analysis (Fig. 7B). FSH stimulation
resulted in an increase in GATA-4 but not GATA-6 message in NT-1 cells.
Forskolin treatment induced expression of both GATA-4 and GATA-6 in
these cells. Collectively, these results establish that GATA-4 mRNA can
be induced by FSH treatment and show that GATA-4 and GATA-6 are
differentially regulated in gonadal cell lines in response to hormone
treatment.
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, B
and C) and TUNEL (Fig. 8A) assays to examine GATA-4 and GATA-6
expression in follicles undergoing programmed cell death. These studies
were carried out on both normal adult ovaries and PMSG/hCG stimulated
juvenile ovaries; identical results were obtained in each case.
Granulosa cells within large and small apoptotic follicles lacked
GATA-4 message (Fig. 8, A and B). In contrast, granulosa cells within
these same follicles continued to express significant levels of GATA-6
message (Fig. 8, A and C).
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)
and GATA-6 (Fig. 9B) mRNA in granulosa cells. There was also
intense expression of GATA-4 message in theca cells and interstitial
cells stimulated for 4 days with DES (Fig. 9A). Consistent with earlier
observations (7), there were few apoptotic cells in ovaries subjected
to continuous estrogen stimulation (Fig. 9C). On the other hand,
ovaries subjected to 2 days of DES followed by 2 days of estrogen
withdrawal contained increased numbers of apoptotic follicles (Fig. 9F). Little GATA-4 mRNA was detected within the granulosa cells of
these apoptotic follicles (Fig. 9D), whereas GATA-6 message was evident
in these same follicles (Fig. 9E). That GATA-6 mRNA expression was
observed in these apoptotic follicles argues that the down-regulation
of GATA-4 message does not merely reflect the end stages of cell death,
but rather part of the programmed response to estrogen withdrawal. In
DES-primed ovaries treated with testosterone, there were large numbers
of severely atretic, TUNEL-positive follicles (Fig. 9I). These
follicles had thin granulosa cell layers, likely reflecting the end
stages of cell death. These severely atretic follicles expressed
neither GATA-4 (Fig. 9G) nor GATA-6 (Fig. 9H) message.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our findings suggest that GATA-4 and GATA-6 play roles in the regulation of ovarian development. On the basis of these expression patterns, we propose that GATA-4 may control genes involved in maturation and/or maintenance of granulosa cells within early follicles (i.e. before ovulation). Alternatively, expression of GATA-4 may serve to prime early follicular cells for the transition to late maturation or apoptosis. The abrupt decrease in GATA-4 associated with ovulation or apoptosis indicates that this factor is not required for the late stages of follicular development, apoptosis, or luteinization. It is possible that GATA-4 functions as a cell survival factor in granulosa cells, analogous to the proposed role of GATA-1 as an antiapoptosis factor in erythroid cells (23). Like GATA-4, transcription factor GATA-6 may regulate genes involved in granulosa cell function. That GATA-6 message is abundantly expressed in granulosa cells both preovulation and post ovulation suggests a unique function for this member of the GATA-binding family in the late stages of follicular development.
Previous studies have documented that GATA-4 and GATA-6 are coexpressed in a variety of tissues, including myocardium and gut epithelium (13, 19, 24, 25, 26, 27, 28, 29, 30, 31). Overlap in the distributions of GATA-4 and GATA-6 transcripts in the heart, gut, and granulosa cells of the ovary raises the possibility of interplay between these two transcription factors. Members of the GATA-binding protein family have been shown to form homodimers (45, 46), heterodimers with other GATA-binding proteins (46, 47), and complexes with other classes of transcription factors (47, 48), including steroid hormone receptors (21, 22). Given their patterns of expression, it is conceivable that GATA-4 and GATA-6 associate with one another or with steroid hormone receptors in granulosa cells of primary and antral follicles, although at present there is no direct evidence to support this hypothesis. That the activity of the prototypical GATA-binding protein, GATA-1, can be modified by heterodimerization with the estrogen receptor (21, 22) raises that possibility that the activity of GATA-4 or GATA-6 in ovarian cells is regulated through interactions with steroid hormone receptors.
Of interest, the "erythroid" transcription factor GATA-1 has been shown to be expressed in a developmental- and stage-specific manner in Sertoli cells of the mouse testes (32, 33), although the target genes for GATA-1 in the testes have not been elucidated. Sertoli cells in the male are functionally analogous to granulosa cells in the female, suggesting that the role of GATA-1 in Sertoli cells may be similar to the role of GATA-4 or GATA-6 in granulosa cells.
Target genes for GATA-4 and GATA-6 in the ovary have not yet been
established, but several genes expressed selectively in ovarian
granulosa cells contain GATA motifs in their promoters (10, 49), as
discussed elsewhere (33). The genes encoding inhibin and aromatase
are of particular interest because these genes are involved in
gonadogenesis and reproduction, are expressed in granulosa cells, and
contain pairs of GATA sites that have been conserved across species.
Whether GATA-4 and GATA-6 act as positive or negative regulators at
these sites is currently unknown. Proof that these and other genes are
bona fide targets for GATA-4 or GATA-6 in vivo awaits formal
genetic tests [e.g. knockout studies or antisense
inhibition experiments (50)].
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Acknowledgments |
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Footnotes |
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2 The first two authors contributed equally to this work.
3 Established Investigator of the AHA.
Received January 13, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-myosin heavy chain gene and
isolation of a human GATA-4 cDNA. Gene 155:219–223[CrossRef][Medline]
-subunit promoter/simian virus T-antigen
fusion gene: characterization of ovarian tumors and establishment of
gonadotropin-responsive granulosa cell lines. Mol Endocrinol 9:616–627[Abstract]
(C/EBP) in the rat ovary:
implications for follicular development and ovulation. Dev Biol 179:288–296[CrossRef][Medline]
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