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Original Studies |
Children’s Hospital (I.K., V.P., L.D., M.H.), Department of Medicine (V.I.), University of Helsinki, 00290 Helsinki, Finland; Departments of Physiology and Pediatrics, University of Turku (J.T.), 20520 Turku, Finland; Departments of Obstetrics and Gynecology (T.V., J.S.T.) and Pathology (R.H.), University of Oulu, 90220 Oulu, Finland; and Department of Pediatrics, Washington University (M.H.), St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Markku Heikinheimo, M.D., Ph.D., Children’s Hospital, Stenbäckinkatu 11, 00290 Helsinki, Finland. E-mail: markku.heikinheimo{at}helsinki.fi
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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GATA-4 messenger ribonucleic acid (mRNA) and protein can be detected in the primitive mouse gonad of both sexes as early as day 11.5 postcoitum. In the developing mouse testis, GATA-4 is expressed in Sertoli and Leydig cells throughout the fetal period (10, 11). In the fetal mouse ovary GATA-4 is expressed in somatic cell lineage until days 13.5–14.5 postcoitum, but it is down-regulated shortly after ovarian differentiation (10). Mullerian inhibiting substance (MIS), an essential factor for the regression of Mullerian ducts in the male, is regulated by GATA-4 in vitro (10). The dimorphic expression pattern of GATA-4 during the fetal period and its role in regulating MIS suggest that GATA-4 participates in early gonadal development and sexual differentiation in mammals (reviewed in Ref. 12).
In our earlier study we found that GATA-4 is expressed in mouse Sertoli and Leydig cells throughout postnatal testicular development (11). Treatment of Leydig or Sertoli tumor cell lines with gonadotropins increases the steady state level of GATA-4 mRNA (11, 13), suggesting hormonal regulation of this transcription factor. Gonadotropin or androgen action is not, however, a prerequisite for the basal expression of GATA-4 in the testis, as the presence of GATA-4 was demonstrated in Sertoli and Leydig cells in genetically hypogonadal (hypogonadotropic) hpg mice, in rats treated with GnRH receptor antagonist, and in rat Sertoli cells after chemical abolition of Leydig cells (11).
Given the emerging role of GATA-4 in the development and regulation of murine testis, we undertook a study on the role of GATA-4 in human testicular development and function. The results elucidate the temporal and spatial expression pattern of GATA-4 in human testis during fetal organogenesis and postnatal development. Using samples from testicular disease and hormonally treated patients, we gained insight into the regulation of GATA-4 in vivo.
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Materials and Methods |
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Fetal testicular tissue samples at weeks 12–19 gestation were
obtained from abortions induced for socio-medical reasons and from
autopsy specimens performed at weeks 22–38 at the Helsinki Maternity
Hospital (Helsinki, Finland) or the Department of Obstetrics and
Gynecology, University of Oulu (Oulu, Finland; Table 1
). Normal juvenile or pubertal testis
biopsy samples were obtained from boys who were diagnosed with acute
lymphoblastic leukemia without testicular involvement. Biopsies were
taken before any treatment with chemotherapy, and no testicular
pathology was discovered. Testis samples from cryptorchid boys were
obtained from diagnostic biopsies during orchidopexy at Children’s
Hospital, University of Helsinki, or Aurora Hospital (Helsinki,
Finland). Undescended testes were located in either inguinal or high
scrotal positions. Fourteen patients had received unsuccessful hCG
treatment, consisting of 10 im injections (500–1000 IU) over a period
of 5 weeks, before surgical treatment. Biopsies were taken 1–4 weeks
after the last hCG injection. In 19 patients the biopsies were taken
before any hormonal therapy. Testicular tissue from patients with
androgen resistance were obtained from therapeutic gonadectomies at
Children’s Hospital.
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Studies were accepted by the ethical committees of Children’s Hospital of University of Helsinki and University of Oulu and were conducted according to the recommendations of the Declaration of Helsinki.
Northern hybridization
Total RNA was isolated using the RNeasy Mini Kit (QIAGEN, Valencia, CA) or the guanidinium thiocyanate method (14) and was analyzed for expression of GATA-4 mRNA using Northern hybridization. Ten micrograms of denatured total RNA were subjected to electrophoresis on 1% or 1.5% denaturing agars gel and then transferred onto nylon membranes (Highland N, Amersham Pharmacia Biotech, Arlington Heights, IL). The membranes were hybridized with 32P-labeled (>6000 Ci/mmol; Amersham Pharmacia Biotech) synthetic oligonucleotide probes for human GATA-4. The sequences of the oligonucleotides were 5'-TTG ACA CAC TCT CTG CCT TCT GAG AAG TCG-3' and 5'-GGC TGT TCC AAG AGT CCT GCT TGG AGC TGG-3', corresponding to nucleotides 919–948 and 1551–1580 of the human GATA-4 mRNA, respectively (GenBank accession no. D78260) (15). To increase the sensitivity of the hybridization, the two oligonucleotides were labeled simultaneously and pooled together in hybridization. Hybridization was performed at 60 C overnight (HB-1 D Hybridizer, Techne, Cambridge, UK) and washed three times for 20 min each time at 60 C with 1 x SSC (standard saline citrate)/0.1% SDS. Hybridization signals were detected by autoradiography using Agfa Curix Ortho ST-L film (Agfa-Gevaert N.V., Mortsel, Belgium). A specific probe for ribosomal 28S mRNA was used as a loading control for Northern hybridization.
Immunohistochemistry
Testicular samples from cryptorchid boys were fixed in Stieve’s fixative, and the other samples were fixed in formalin or 4% paraformaldehyde. They were then embedded in paraffin. Tissue sections (5 µm) were subjected to immunohistochemistry using commercial polyclonal goat antimouse GATA-4 IgG (1:100 dilution; sc-1237, Santa Cruz Biotechnology, Inc., Santa Cruz, CA), nonimmune IgG, or secondary antigoat antibody as the primary antibody. The avidin-biotin immunoperoxidase system was used to visualize bound antibody (Vectastain Elite ABC Kit, Vector Laboratories, Inc., Burlingame, CA). 3-Amino-9-ethylcarbazole (Sigma, St. Louis, MO) was used as the chromogen, and the development reaction occurred in the presence of 0.03% H2O2. Samples were analyzed by light and phase contrast microscopy (DMRXA microscope, Leica Corp. AG, Heerbrugg, Switzerland).
Western blot analysis
Small tissue sections were homogenized on ice in homogenization buffer [1% Triton X-100, 150 mmol/L NaCl, 10 mmol/L Tris (pH 7.4), 1 mmol/L ethylenediamine tetraacetate, 1 mmol/L ethyleneglycol-bis-(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid, 0.2 mmol/L sodium ortho-vanadate, 0.2 mmol/L phenylmethylsulfonylfluoride, and 1 mg/ml leupeptin]. After centrifugation at 17,000 x g at 4 C for 30 min, the supernatants were collected, and their protein concentrations were determined by the DC protein assay (Bio-Rad Laboratories, Inc., Hercules, CA). Proteins (40 g) were loaded onto a 10% SDS-polyacrylamide gel, and electrophoresis was performed at 160 V in the presence of a Rainbow marker standard (Amersham Pharmacia Biotech). The proteins were transferred to polyvinylidene difluoride membrane (Immobilon-P, Millipore Corp., Bedford, MA) by electrophoresis for 2 h at 4 C in transfer buffer (26 mmol/L Tris, 192 mmol/L glycine, and 10% methanol) at 100 V. The transfer was checked by staining with 0.2% Ponceau S in 3% trichloroacetic acid. GATA-4 protein on the membrane was detected using an affinity-purified rabbit polyclonal antibody to GATA-4 (16) at a dilution of 1:1000, followed by horseradish peroxidase-conjugated secondary antibody (Jackson ImmunoResearch Laboratories, West Grove, PA). The bound secondary antibody was located with the ECL detection kit (Amersham Pharmacia Biotech).
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Results |
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Northern blot analysis demonstrated GATA-4 mRNA in the fetal
testis at 15 weeks gestation, and it remained evident to adulthood
(Fig. 1A). The presence of GATA-4 protein
in adult human testis was shown by Western blot analysis; all 15
samples studied were positive for GATA-4 (Fig. 1B).
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and Fig. 2, A–F). However, some of the primordial
germ cells were GATA-4 negative. During fetal development, GATA-4
staining intensity was stronger in the testicular cords than in the
interstitium. The staining intensity in the Sertoli cells was most
intensive at weeks 19–22 (Fig. 2D) and declined thereafter. In Leydig
cells, GATA-4 immunoreactivity was strongest at the end of the first
trimester, at week 15 (Fig. 2B), and declined toward the end of the
fetal period.
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, G and H). The
staining intensities in prepubertal Sertoli cells and spermatogonia
were equal, although some spermatogonia remained negative. After
puberty, GATA-4 expression was not detected in the germ cells (Fig. 2, J and K). The Leydig cells became more intensively GATA-4 positive at
puberty and remained positive thereafter, although the number of
positive Leydig cells decreased with advancing age (Figs. 2J and 4C).
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GATA-4 expression was studied in testes of patients who underwent
orchidectomy due to androgen resistance (Table 1). In these samples,
the staining intensity in the Sertoli cells and spermatogonia was
either very weak or totally absent, and it decreased along with
advancing age from 1–14 yr (Fig. 3, A–C). Leydig cells were negative for GATA-4, but due to variable
testicular morphology in androgen resistance, we cannot exclude the
possibility that some of the interstitial Leydig cells were GATA-4
positive. No difference in GATA-4 expression could be seen between
testicular samples from patients with partial and those with complete
androgen resistance.
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). In cryptorchid testes,
GATA-4 immunoreactivity was present in the Sertoli cells and
spermatogonia, but it was very weak or absent in the Leydig cells (Fig. 3, D and E); these findings are comparable to the expression pattern in
normal testis. The treatment used, the localization of the testis, and
the time from treatment to biopsy did not have any effect on GATA-4
expression in any testicular cell type.
In an adult patient with Kallman’s syndrome, Sertoli and Leydig cells
were positive whereas spermatogonia were negative for GATA-4 (Fig. 4A). The staining intensity in Sertoli
and Leydig cells appeared weaker than that in normal testes (Fig. 4B).
We also obtained testicular tissue from a patient treated with GnRH
agonist and antiandrogen for prostate cancer. In this sample, GATA-4
protein was abundantly expressed in the Sertoli cells, but the
expression of GATA-4 was very faint or totally absent in the remaining
Leydig cells (Fig. 4C). In addition, we studied testicular samples from
patients who had received hormonal treatment for prostate cancer with
GnRH agonist only. The treatment appeared to be inadequate, as normal
spermatogenesis was found, indicating insufficient androgen production
suppression. In these samples GATA-4 expression was equal in Sertoli
and Leydig cells, whereas all types of germ cells remained negative
(data not shown).
GATA-4 expression in Sertoli and Leydig cell tumors
Sertoli tumor cells showed very intense expression of GATA-4 in
the testis from a 12-yr-old boy with a Sertoli cell tumor (large cell
calcifying Sertoli cell tumor; Fig. 5, A
and B). Normal Sertoli and Leydig cells also expressed GATA-4, but the
staining intensity in Sertoli tumor cells was clearly stronger than
that in Sertoli cells in the adjacent healthy tubules. This finding was
consistent in all affected tubuli. Spermatogenesis had already advanced
up to haploid stage, and all types of germ cells were negative for
GATA-4 protein.
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).
Unaffected interstitial Leydig cells and tubular Sertoli cells stained
as in control samples. |
Discussion |
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Germ cells in the fetal testis expressed GATA-4, and the expression was also found in spermatogonia of prepubertal boys. After puberty, the expression of GATA-4 protein was totally abolished in all types of germ cells. The present results are in agreement with our previous study showing that murine germ cells are devoid of GATA-4 after puberty (11). On the contrary, Viger et al. (10) reported expression of GATA-4 protein in murine germ cells after puberty. The possible species-specific differences and the reason for GATA-4 down-regulation in the human germ cells after puberty remain to be evaluated.
In Sertoli cells, GATA-4 is expressed throughout fetal and postnatal development. Given that Sertoli cells proliferate only during the fetal and prepubertal periods, the very intense GATA-4 expression in fetal and prepubertal Sertoli cells suggest a role for this transcription factor in the proliferation of these testicular supportive cells. In fetal Sertoli cells, the strongest GATA-4 expression level coincides with high serum FSH levels at the beginning of the second trimester (17), suggesting that in vivo, GATA-4 may be under gonadotropic control already during the fetal period. This assumption is compatible with our previous findings demonstrating up-regulation of GATA-4 mRNA by FSH in mouse Sertoli tumor cell lines (13).
Only a few prepubertal Leydig cells showed weak GATA-4 expression, whereas after puberty GATA-4 expression was clearly evident. The fact that Leydig cell testosterone production starts at puberty, coinciding with increasing GATA-4 expression, suggests a link between GATA-4 and androgen production. A connection between GATA-4 and steroidogenesis is also supported by the idea that Leydig cell GATA-4 expression during the fetal period was most intensive at week 15 postcoitum, when fetal testosterone production is at its peak (18). Furthermore, GATA-4 was low or absent in Sertoli cells in patients with androgen resistance, suggesting that androgen action could influence GATA-4 expression.
In cryptorchid testes, hCG treatment did not have an effect on the GATA-4 expression pattern in Sertoli, Leydig, or germ cells. However, short-term effects of hCG treatment on GATA-4 expression cannot be ruled out, because testicular biopsies were performed 1–4 weeks after hCG treatment, when circulating testosterone levels had already decreased significantly. In the testes of one 65-yr-old man treated with GnRH agonist and antiandrogen, GATA-4 expression in the remaining Leydig cells was markedly lower than that in untreated men. Whether this is a result of down-regulated pituitary gonadotropin secretion and/or physiological changes related to aging remains unclear. Furthermore, in this testicular sample GATA-4 expression in Sertoli cells was more intense than in the control samples. Intense GATA-4 expression may be due to a direct stimulatory effect of GnRH agonist on Sertoli cells. These results in human testes are in agreement with findings in rodent testes after GnRH receptor antagonist treatment or chemical abolition of Leydig cells; in these experimental models GATA-4 expression remained unchanged in Sertoli cells (11).
In light of the findings presented in this report, we propose that a normal testicular response to gonadotropins as well as androgen action are needed for normal GATA-4 expression in the human testis, particularly in Leydig cells. However, gonadotropin and/or androgen actions are not prerequisites for the basal expression of GATA-4 in Sertoli and germ cells. A gonadotropin stimulus may be more important for GATA-4 expression during fetal development than postnatally, given that hCG treatment of cryptorchid boys had no effect on GATA-4 expression in Sertoli and germ cells. It is, however, most likely that not only gonadotropins and androgens but other factors as well may be involved in the regulation of GATA-4 in Sertoli and Leydig cells.
GATA-4 expression was intense in the two types of testicular somatic cell tumors, Sertoli and Leydig cell tumors. In our unpublished studies we have not detected GATA-4 in germ cell-derived tumors, i.e. seminomas. GATA-4 was recently discovered in a subset of cells in testicular yolk sac tumors (19), but there are no other reports of GATA-4 expression in gonadal malignancies. Our recent observations also reveal strong GATA-4 expression in ovarian granulosa and thecal cell tumors, i.e. tumors arising from ovarian counterparts for testicular Sertoli and Leydig cells, respectively (19A ). These observations propose that GATA-4 may influence cell proliferation during tumorigenesis in human somatic cell-derived gonadal tumors. This idea is in line with the observation of intense GATA-4 expression during the proliferative phase in mouse Sertoli cells (Refs. 10, 11 and this study). Enhanced or persistent expression of GATA-4 has been reported with nongonadal tumors, including adrenocortical carcinomas (20), and esophageal/gastric adenocarcinomas (21), supporting a role for this transcription factor in the progression of certain neoplasms.
The present study reveals developmental changes in the expression of
the transcription factor GATA-4 in the human testis. Furthermore, our
results reveal a temporal relationship between GATA-4 and
steroidogenesis in human Leydig cells, and that GATA-4 may be regulated
by FSH in fetal Sertoli cells. Previous studies have indicated GATA-4
to be a potent trans-activator of several important
testicular genes, including MIS (10), inhibin-
(11), and
steroidogenic acute regulatory protein (22). These in vitro
observations suggest a role for GATA-4 in the regulation of central
testicular genes. More rigorous tests, including the use of
tissue-specific knockout animals, might shed light on the significance
of GATA-4 in the testis. Unfortunately, mice carrying a null mutation
for Gata4 suffer from early embryonic lethality, precluding
their use in assessing the role of GATA-4 in the gonad. It will also be
important to reveal the expression patterns of known cofactors for
GATA-4, such as FOG-2 (23, 24, 25), in the gonad. Earlier work demonstrated
that another GATA-binding protein, GATA-6, has overlapping, but
distinct, expression with that of GATA-4 in the murine testis (11).
GATA-6 and GATA-1, expressed in testicular Sertoli cells (26), may also
have important roles in certain testicular cell types and may function
in concert with GATA-4 to regulate testicular development and
function.
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Acknowledgments |
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Footnotes |
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Received March 1, 2000.
Revised May 22, 2000.
Accepted June 20, 2000.
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