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Review |
From the Ontogeny-Reproduction Research Unit, CHUL Research Centre, and Centre de Recherche en Biologie de la Reproduction (CRBR), Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Ste-Foy, Québec, Canada.
| Correspondence to: Dr Robert S. Viger, Ontogeny-Reproduction, Room T1-49, CHUL Research Centre, 2705 Laurier Blvd, Ste-Foy, Québec, Canada G1V 4G2 (e-mail: Robert.Viger{at}crchul.ulaval.ca). |
| Received for publication January 29, 2004; accepted for publication February 4, 2004. |
The GATA Family of Transcription Factors
GATA regulatory elements and their prototypic binding protein were
originally identified in studies of erythroid-specific gene expression more
than a decade ago (Orkin,
1992; Weiss and Orkin,
1995a). A novel transcription factor that specifically bound to
GATA cis-elements was cloned from erythroid cells and named GATA1
(Tsai et al, 1989). GATA1 was
shown to contain a DNA-binding domain that consisted of two similar zinc
fingers with the distinctive form
C-X2-C-(X17)-C-X2-C
(Tsai et al, 1989; Weiss and Orkin, 1995a).
Since the cloning of the prototypic GATA1 factor, 5 additional vertebrate
factors (named GATA2 to GATA6), having similar DNA-binding domains, have been
identified (Weiss and Orkin,
1995a; Molkentin,
2000). The 6 vertebrate GATA factors can be separated into 2
subgroups based on sequence homology and tissue distribution: the
hematopoietic (GATA1/2/3) and the cardiac (GATA4/5/6) GATA factors
(Figure 1).
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Expression and Role of GATA Factors Outside of the Reproductive System: GATA1/2/3— The GATA1 gene is abundantly expressed in erythroid and megakaryotic cells (Orkin, 1992; Weiss and Orkin, 1995a). Consistent with this localization, consensus GATA-binding motifs are found in several genes specifically expressed in these cell lineages. Gene knockout experiments in mice have revealed that Gata1 is required for embryonic viability, since its expression is crucial for the terminal differentiation of erythroid precursors and the growth and maturation of megakaryocytes both in vitro and in vivo (Pevny et al, 1991; Fujiwara et al, 1996; Shivdasani et al, 1997). Erythroid precursor cells lacking Gata1 fail to mature and undergo either extensive apoptosis (Pevny et al, 1995; Weiss and Orkin, 1995b) or deregulated proliferation (Shivdasani et al, 1997). In addition to hematopoietic cells, the GATA1 gene is also abundantly transcribed in the testis (described in detail later). Like GATA1, GATA2 is present in hematopoietic cells but is also found in several nonhematopoietic lineages such as endothelial cells, fibroblasts, Wolffian ducts, pituitary, and embryonic brain and liver cells (Yamamoto et al, 1990; Lee et al, 1991; Gordon et al, 1997; Zhou et al, 1998; Dasen et al, 1999). Similarly, GATA3 expression is not limited to hematopoietic cells (T-lymphocytes and definitive erythroid cells) but is also found in several other embryonic tissues, including the placenta, brain, kidney, and thymus (Leonard et al, 1993; Kornhauser et al 1994; George et al, 1997). Although GATA1/2/3 have overlapping expression patterns in hematopoietic cell lineages, the knockout of their corresponding genes produce distinct phenotypes in mice (Tsai et al, 1994; Pandolfi et al, 1995; Fujiwara et al, 1996; Ting et al, 1996). The absence of the Gata2 factor produces a defect in which early hematopoietic cells fail to proliferate (Tsai et al, 1994). Interestingly, a rescue of the embryonic-lethal hematopoietic defect in the Gata2 knockout mouse using yeast artificial chromosomes (YAC) has revealed a critical role for this factor in the development of tissues that derive from the Wolffian duct, such as the seminal vesicles and vasa deferentia (described further below)(Zhou et al, 1998). Finally, mice embryos containing homozygous mutations in the Gata3 gene die between 11 and 12 days postcoitum as a result of massive internal hemorrhaging and severe brain and spinal cord deformities (Pandolfi et al, 1995). Mice lacking the Gata3 gene also exhibit a hematopoietic defect in which the development of mature T-lymphocytes is arrested (Ting et al, 1996).
GATA4/5/6— Unlike their counterparts in hematopoietic cells, members of this GATA factor subfamily exhibit strong expression in the stomach, gut epithelium, heart, and gonads (Arceci et al, 1993; Kelley et al, 1993; Tamura et al, 1993; Grépin et al, 1994; Heikinheimo et al, 1994, 1997; Laverriere et al, 1994; Morrisey et al, 1996, 1997; Bossard and Zaret, 1998; Viger et al, 1998; Ketola et al, 1999; Robert et al, 2002; Nemer and Nemer, 2003). The GATA4 gene is abundantly expressed in the developing heart (Kelley et al, 1993; Heikinheimo et al, 1994). Consequently, GATA4 has been indicated as a key regulator of cardiac-specific gene expression during development. Indeed, functional GATA-binding elements have been identified in the promoters of several cardiac-specific genes that are activated by GATA4 in noncardiac cells (Grépin et al, 1994; Ip et al, 1994; Molkentin et al, 1994; Parmacek et al, 1994). The characterization of Gata4 knockout mice, which die between embryonic days 6.5 to 8.0 because of defects in heart tube formation, has confirmed the importance of this factor in heart development (Kuo et al, 1997; Molkentin et al, 1997). Moreover, GATA4 is associated with human heart disease, in which case it acts as a novel transcriptional regulator of calcineurin-dependent cardiac hypertrophy (Molkentin et al, 1998), and mutations in the GATA4 gene have been recently linked to congenital heart defects (Garg et al, 2003). In addition to the heart, GATA4 is also prominently expressed in the developing gonads, including Sertoli and Leydig cells of the testis (described below). During embryogenesis, GATA5 is first expressed in the developing heart and subsequently in the lung, vasculature, and genitourinary system (Morrisey et al, 1997; Molkentin et al, 2000; Nemer and Nemer, 2003). GATA6 is expressed in multiple cell lineages derived from lateral mesoderm, including the heart, gut, and gonads (Morrisey et al, 1996; Ketola et al, 1999; Robert et al, 2002; Nemer and Nemer, 2003). Targeted inactivation of the Gata5 and Gata6 genes has revealed that these factors serve distinct physiological roles in vivo (Morrisey et al, 1998; Koutsourakis et al, 1999; Molkentin et al, 2000). Inactivation of the Gata6 gene causes early embryonic lethality shortly after implantation as a result of a lack of endoderm differentiation and/or extraembryonic tissue (Morrisey et al, 1998; Koutsourakis et al, 1999). Although loss of Gata5 function does not lead to embryo death, female Gata5-/- mice exhibit pronounced genitourinary abnormalities that include vaginal and uterine defects and hypospadias (Molkentin et al, 2000). Taken together, the mouse knockout data have revealed that GATA factors play critical developmental roles. Indeed, aberrations in GATA function have now been recently linked with human disease, where a mutation of the GATA1 gene has been associated with dyserythropoietic anemia and thrombocytopenia (Nichols et al, 2000), GATA3 haplo-insufficiency with human hypoparathyroidism, sensorineural deafness, renal anomaly (HDR) syndrome (Van Esch et al, 2000), and GATA4 mutations with congenital heart defects (Garg et al, 2003).
Functional Specificity of GATA Factors— All vertebrate GATA proteins contain a conserved DNA-binding domain composed of two multifunctional zinc fingers. The C-terminal zinc finger is required for site-specific recognition and DNA-binding to the core GATA motif, whereas the N-terminal zinc finger contributes to the specificity and stability of the DNA-binding (Martin and Orkin, 1990; Yang and Evans, 1992; Omichinski et al, 1993). Since members of the GATA family share a highly conserved DNA-binding domain, they all exhibit similar DNA-binding properties (Ko and Engel, 1993; Merika and Orkin, 1993). This contrasts, however, with their rather specific roles in vivo (Pevny et al, 1991; Tsai et al, 1994; Blobel et al, 1995; Pandolfi et al, 1995; Kuo et al, 1997; Molkentin et al, 1997, 2000; Morrisey et al, 1998; Zhou et al, 1998; Koutsourakis et al, 1999; Takahashi et al, 2000). The specificity of GATA action is controlled, at least in part, via protein-protein interactions with other transcriptional partners (Charron and Nemer, 1999; Molkentin, 2000). Indeed, there is now an extensive list of ubiquitously expressed or cell-restricted factors that are known to cooperate with GATA factors to control tissue-specific transcription in the hematopoietic system, the heart, the pituitary, the adrenal, and the gonads (Kawana et al, 1995; Merika and Orkin, 1995; Osada et al, 1995; Gregory et al, 1996; Durocher et al, 1997; Gordon et al, 1997; Lee et al, 1998; Ono et al, 1998; Rekhtman et al, 1999; Tremblay and Viger, 1999; Morin et al, 2000; Nerlov et al, 2000; Tremblay et al, 2002; Jimenez et al, 2003). Of the different GATA-interacting factors, the most notable are the multitype zinc finger proteins termed Friend of GATA1 (FOG1) and Friend of GATA2 (FOG2), because the FOG proteins were originally identified as GATA-specific cofactors through their ability to interact with the N-terminal zinc fingers of the different GATA factors (Tsang et al, 1997; Holmes et al, 1999; Lu et al, 1999; Svensson et al, 1999; Tevosian et al, 1999). Like GATA1, FOG1 is highly expressed in hematopoietic cell lineages (Tsang et al, 1997). Similarly, FOG2 is coexpressed with GATA4 in the heart, brain, and gonads (Lu et al, 1999; Tevosian et al, 1999; Laitinen et al, 2000; Ketola et al, 2002; Robert et al, 2002; Anttonen et al, 2003). Mouse knockout studies have revealed that FOG proteins, like their GATA counterparts, have crucial developmental functions in vivo. Thus, the lack of Fog1 leads to a block in erythroid and megakaryocytic differentiation (Tsang et al, 1998), while genetic ablation of Fog2 leads to defects in heart morphogenesis and coronary vascular development (Svensson et al, 2000b; Tevosian et al, 2000; Crispino et al, 2001), as well as impaired gonad development (Tevosian et al, 2002). Although the FOG proteins do not appear to directly bind to DNA, they act as either enhancers or repressors of GATA transcriptional activity depending on the cell context and promoter being studied (Tsang et al, 1997; Fox et al, 1999; Holmes et al, 1999; Lu et al, 1999; Svensson et al, 1999, 2000a; Tevosian et al, 1999; Robert et al, 2002). The role of FOG proteins in modulating GATA-dependent transcription in the testis will be discussed later.
Expression of GATA Factors in the Male Reproductive System
As previously mentioned, GATA factors are not unique to the hematopoietic
and cardiac systems but rather are expressed in a wide variety of tissues.
This includes tissues of both the male and female reproductive tracts, with
the predominant sites of expression being the testis and ovary. GATA-like
DNA-binding proteins are found in the gonads of species ranging from worms to
humans (Spieth et al, 1991;
Tamura et al, 1993;
Drevet et al, 1994; Laverriere et al, 1994;
Singh et al, 1994;
Yomogida et al, 1994; Lossky and Wesink, 1995;
Heikinheimo et al, 1997;
Viger et al, 1998;
Ketola et al, 1999;
De Santa Barbara et al, 2000), suggesting that a functional role for GATA factors in the gonads has been
conserved during evolution. Of the 6 vertebrate GATA factors, 4 are expressed
in the mammalian gonads: GATA1 (Ito et al,
1993; Yomogida et al,
1994; Viger et al,
1998), GATA2 (Siggers et al,
2002), GATA4 (Heikinheimo et
al, 1997; Viger et al,
1998; Ketola et al,
1999; McCoard et al,
2001), and GATA6 (Heikinheimo
et al, 1997; Ketola et al,
1999; Robert et al,
2002). As a general rule, GATA factors label the major somatic
cell types of the gonads. The exceptions are GATA2, which is expressed
specifically in germ cells of the mouse ovary during a very discrete period of
early fetal development (Siggers et al,
2002), and GATA4, which, in addition to labeling somatic cells,
has also been reported to be strongly expressed in fetal and prepubertal germ
cells of the human testis (Ketola et al,
2000). The significance of GATA expression in germ cells, however,
has yet to be demonstrated.
GATA Factors in the Testis: GATA1— The mammalian testis expresses 3 GATA factors: GATA1, GATA4, and GATA6 (Table). Because of the functional importance of GATA proteins in other systems, these factors have emerged as a group of potentially important regulators of testicular gene expression and function. GATA1 was the first GATA factor shown to be expressed in the testis (Ito et al, 1993; Yomogida et al, 1994). To date, it is also the only GATA factor whose expression in the testis is known to be driven by a testis-specific promoter (Onodera et al, 1997). In the mouse, testicular Gata1 expression is restricted to Sertoli cells of postnatal animals (Yomogida et al, 1994; Viger et al, 1998; Ketola et al, 2002). Expression begins in the prepubertal testis, where Sertoli cells uniformly express the protein (Yomogida et al, 1994). After puberty, however, the number of Gata1-expressing seminiferous tubules show a stage-specific decline, so that by adulthood, only Sertoli cells in stage VII, VIII, and IX tubules exhibit Gata1 immunoreactivity (Yomogida et al, 1994). In addition to postnatal Sertoli cells, recent data by Chen et al have suggested that Leydig cells might also express GATA1 (Zhang et al, 2002). This was based on Northern blot data of RNA obtained from MA-10 Leydig tumor cells and an enriched population of 21-day-old rat progenitor Leydig cells (Zhang et al, 2002). Further in situ hybridization or immunohistochemistry data is needed, however, to confirm that GATA1 is indeed expressed in Leydig cells in vivo.
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GATA4— Testicular expression of the GATA4 transcription factor has been well-documented in 3 different species: mouse, pig, and human (Viger et al, 1998; Ketola et al, 1999, 2000; McCoard et al, 2001). In the mouse and pig, GATA4 is abundantly expressed from the onset of gonadal development, where it labels virtually all cell types present with the notable exception of germ cells (Viger et al, 1998; McCoard et al, 2001). After gonadal differentiation, GATA4 expression is maintained at high levels in the fetal testis in both Sertoli cells and interstitial (Leydig) cells (Viger et al, 1998; McCoard et al, 2001). In the mouse, Sertoli cells continue to express Gata4 after birth, but levels decline in adulthood, when Gata1 becomes the predominant GATA factor (Viger et al, 1998). GATA4 is also abundantly expressed by the MSC-1 Sertoli cell line (Heikinheimo et al, 1997; Robert et al, 2002). Much like Sertoli cells, GATA4 expression in Leydig cells persists in the developing mouse and porcine testis through to adulthood (Ketola et al, 1999; McCoard et al, 2001), and GATA4 is a marker of several transformed and/or immortalized Leydig cell lines (Ketola et al, 1999; Robert et al, 2002; Zhang et al, 2002). In the human testis, GATA4 expression parallels what has been observed in the mouse and pig, with one exception: germ cells (Ketola et al, 2000). Unlike the mouse and pig, GATA4 appears to be a major GATA factor of both fetal and prepubertal human male germ cells (Ketola et al, 2000).
GATA6— Along with GATA1 and GATA4, GATA6 is the third GATA factor shown to have predominant expression in Sertoli cells. In the mouse, Gata6 expression overlaps with Gata4 in Sertoli cells during fetal and early postnatal development (Viger et al, 1998; Ketola et al, 1999; Robert et al, 2002). All 3 GATA factors (Gata1/4/6), however, are coexpressed in Sertoli cells of the adult testis (Yomogida et al, 1994; Viger et al, 1998; Ketola et al, 1999; Robert et al, 2002;). In rodents, Gata6 expression appears to be specific to Sertoli cells, whereas in humans, GATA6 is detected in both Sertoli and Leydig cells at least in the fetal testis (Ketola et al, 2003).
Other Androgen-Dependent Tissues— Aside from the testis, little attention has been given to the expression of GATA factors in the other tissues that compose the male reproductive tract. At present, it is unclear whether the absence of such reports can be construed as a lack of expression or merely a lack of investigation. Nonetheless, there is at least one report of GATA expression in the prostate, coagulating gland, and seminal vesicle (Perez-Stable et al, 2000). Normal mouse and human prostate were shown to express both GATA2 and GATA3 (Perez-Stable et al, 2000). Although no other GATA factor was detected in normal prostate, weak GATA6 expression was found in the human PC-3 and ALVA-31 prostate cancer cell lines (Perez-Stable et al, 2000). The GATA2 gene was also shown to be abundantly transcribed in the androgen-dependent LNCaP prostate cancer cell line (Perez-Stable et al, 2000). The same group also identified several GATA elements in the human KLK3 (prostate-specific antigen) gene enhancer, suggesting that GATA factors might be involved in the androgen-dependent regulation of the KLK3 gene in the prostate.
The two other sites of significant GATA expression in the male reproductive system are the Wolffian ducts (precursors of the seminal vesicles, epididymides, and vasa deferentia) and the genital tubercle. Gata3 expression in the developing genital tubercle (primordium of the penis in males) was found serendipitously while studying the temporal and spatial control of the murine Gata3 promoter in transgenic mice (Lieuw et al, 1997). Although targeted inactivation of the Gata2 in mice leads to midgestational death (Tsai et al, 1994), rescue of the lethal hematopoietic defect revealed an expected role for Gata2 in urogenital development (Zhou et al, 1998). Despite normal appearing testes and epididymides, the Gata2 mutant males frequently had hypoplastic seminal vesicles that were aberrantly fused to the vasa deferentia (Zhou et al, 1998). This interesting finding prompted the investigators to look more closely at Gata2 expression in the developing urogenital system. Consistent with their observed phenotype, Gata2 expression in males was found to be strongly expressed in the Wolffian ducts. However, unlike the prostate and especially the testis, which is described next, target genes for GATA2 in the Wolffian duct derivatives have yet be identified.
GATA Factors in the Testis: Functional Roles and Target Genes
Although gene inactivation experiments have identified crucial roles for
GATA factors in early vertebrate development, they have been less useful for
the study of their later recruitment as regulators of tissue-specific gene
expression in vivo, since 5 out of the 6 Gata-/- mice are
embryonic lethal. This includes the Gata1/4/6 gene knockouts, in
which embryo death occurs prior to testis development
(Pevny et al, 1991;
Kuo et al, 1997; Molkentin et al, 1997;
Morrisey et al, 1998). To
assess the role of these factors in the testis, a selective inactivation or
knockdown of GATA function is therefore essential. These types of experiments
have begun to be used to gain insights into the in vivo testicular roles
played by GATA1 and GATA4 (Tevosian et al,
2002; Lindeboom et al,
2003). As previously mentioned, the Gata4 gene is
abundantly expressed in the somatic cell population of the developing mouse
genital ridge around the time of sex determination. Thus, based on its
expression pattern, GATA4 was proposed to play a central role in sex
determination and, hence, testis differentiation. This hypothesis has been
recently confirmed in the mouse, in which in vivo disruption of one of Gata4's
functions (interaction with its co-factor Fog2) via an elegant knock-in
mutation of the Gata4 gene leads to a block in testis development and
a marked down-regulation of expression of the testis-determining gene,
Sry (Tevosian et al,
2002). Thus, GATA4 appears to function as an upstream regulator of
SRY expression in the developing testis. Although the latter has yet
to be conclusively demonstrated, the presence of multiple GATA regulatory
motifs in the mouse, human, and pig SRY promoters strongly supports
this notion.
By creating a conditional knockout allele of the Gata1 gene and using the Desert Hedgehog promoter driving Cre recombinase to excise the floxed Gata1 gene in Sertoli cells, Lindeboom et al (2003) recently reported the first testis-specific knockout of a GATA gene. Surprisingly, Gata1 null testes were morphologically and functionally normal (Lindeboom et al, 2003). The absence of an overt testicular phenotype was likely due to compensation by Gata4 and Gata6 in Sertoli cells, which masked the loss of Gata1. A global knockout or knockdown of GATA activity would therefore be needed to assess the functional role of GATA factors in postnatal Sertoli cells in which overlapping expression of multiple GATA factors poses a problem.
The lack of conditional knockout models has not stopped investigators from gaining insights into the potential role played by GATA factors in the testis. The fact that GATA factors recognize specific regulatory motifs (WGATAR) in the promoter regions of genes has been exploited to identify novel targets for these factors in many tissues, including the testis. The Müllerian inhibiting substance (MIS or AMH) promoter was identified as the first known target for GATA4 in Sertoli cells (Viger et al, 1998). The MIS hormone is the earliest marker of testis formation. It regulates male sex differentiation by triggering regression of the Müllerian ducts (the precursors of the female reproductive tract) in males (Teixeira et al, 2001). MIS gene expression is tightly regulated during gonadal development; lack of expression in humans causes persistent Müllerian duct syndrome, a condition in which affected males exhibit both male and female internal reproductive organs. Through an analysis of the conserved 5' regulatory elements of the MIS gene, several transcription factors have been proposed to participate in MIS transcription, such as the nuclear receptor steroidogenic factor 1 (SF1) and the high mobility group box-containing protein SOX9 (Shen et al, 1994; Giuili et al, 1997; Arango et al, 1999). However, since SOX9 and SF1 are colocalized in several tissues that do not express MIS, other factors must act to restrict MIS expression to the gonads. Indeed, cooperation between transcription factors has been shown to contribute to tissue-specific MIS expression (Teixeira et al, 2001); this includes GATA4 (Tremblay and Viger, 1999; Watanabe et al, 2000; Tremblay et al, 2001). GATA4 has been shown to regulate both the mouse and human MIS promoters through a transcriptional cooperation with SF1 (Tremblay and Viger, 1999; Watanabe et al, 2000). Although no human GATA4 gene mutations have yet been linked to gonadal defects, recent evidence suggests that disruption of GATA4/SF1 synergism may account for some cases of abnormal human male sex differentiation involving insufficient MIS expression (Tremblay and Viger, 2003a).
The overlapping expression of multiple GATA factors in Sertoli cells is a
strong indication that these GATA factors are key regulators of Sertoli
cell–specific gene expression and function during ontogeny. Indeed, in
addition to MIS, GATA factors have been shown to regulate several
Sertoli-cell promoters (Table).
These include the inhibin 
(Inha;
Feng et al, 1998;
Ketola et al, 1999;
Tremblay and Viger, 2001a),
inhibin/activin ßB (Inhbb;
Feng et al, 2000),
Sf1 (Tremblay and Viger,
2001a), follicle-stimulating hormone (FSH) receptor
(Fshr; Kim and Griswold,
2001), Doublesex- and Mab-3–related transcription factor
(Dmrt1; Lei and Heckert,
2004), and Sry (Viger et al, unpublished data) promoters.
In vitro studies by Feng et al have shown that the inhibin promoter is
preferentially activated by GATA1 despite the colocalization of GATA1 and
GATA4 in Sertoli cells (Feng et al,
1998,
2000). However, since all GATA
factors are known to have similar DNA-binding properties
(Merika and Orkin, 1993),
selectivity based on transactivation properties alone would seem unlikely.
Rather, whether a Sertoli cell gene responds or not to regulation by a
particular GATA factor would likely depend on cooperative interactions with
specific transcriptional partners acting as either coactivators or
corepressors.
Besides Sertoli cells, GATA are also prominently expressed in the interstitial cell (steroidogenic) compartment of the testis (Table). Although both GATA4 and GATA6 are expressed in ovarian steroidogenic cells throughout development (Heikinheimo et al, 1997; Laitinen et al, 2000), in the testis, GATA4 is the predominant GATA factor of both fetal and postnatal Leydig cells (Viger et al, 1998; Ketola et al, 1999, 2000). Thus, GATA factors, and in particular GATA4, have been proposed to be key regulators of steroidogenesis in the testis (Tremblay and Viger, 2003b). In support of this hypothesis, the promoters of several steroidogenic enzyme-encoding genes have been reported to contain one or more consensus GATA regulatory motifs (Tremblay and Viger, 2003b). Using in vitro transactivation experiments, several laboratories have confirmed that some of these steroidogenic promoters are indeed targets for GATA factors. Those studied to date include the promoters for Sf1 (Tremblay and Viger, 2001a), 17ß-hydroxysteroid dehydrogenase type 1 (HSD17B1; Piao et al, 1997), P450 aromatase (Cyp19; Tremblay and Viger, 2001a), steroidogenic acute regulatory protein (Star; Silverman et al, 1999; Wooton-Kee and Clark, 2000; Tremblay and Viger, 2001a; Tremblay et al, 2002), and 3ß-hydroxysteroid dehydrogenase type 2 (HSD3B2; Viger et al, unpublished data). In addition to their ability to directly stimulate transcription of target steroidogenic promoters, GATA factors also contribute to the tissue-specific activity and hormone dependence of some of these promoters via synergistic interactions with the orphan nuclear receptor SF1 and the CCAAT enhancer binding protein C/EBPß (Tremblay and Viger, 2003b).
Regulation of GATA Expression and Transcriptional Activity in the Testis
Although the list of target genes for GATA factors in testicular cells
continues to grow, much less is known about how GATA expression itself is
regulated in the testis. Yomigida et al (1994) observed that Sertoli cell
expression of Gata1 is increased in germ cell–deficient mouse
models, suggesting that GATA1 expression in the testis is negatively regulated
by one or more paracrine factors produced by germ cells. The concept of a
"negative regulation" of GATA1 in the testis has resurfaced
recently with the demonstration that Gata1 expression in both MA-10
Leydig cells and primary Sertoli cell cultures is markedly down-regulated by
FSH/cAMP treatment (Zhang et al,
2002). Interestingly, the inhibitory effect was specific for
testicular cells, since Gata1 expression in erythroid cells was unaffected
under similar conditions. At present, however, the physiological significance
of this gonadotropin/cAMP–mediated regulation remains unclear. In
contrast to GATA1, gonadotropins and/or cAMP agonists have been shown to
induce Gata4 and/or Gata6 expression in several gonadal cell
lines, including MSC-1 Sertoli cells and mLTC-1 Leydig cells
(Heikinheimo et al, 1997;
Ketola et al, 1999). In
humans, the stimulatory role of FSH in the regulation of GATA4 is supported,
at least in the ovary, by the association of an inactivating mutation of the
FSH receptor with greatly diminished GATA4 expression
(Vaskivuo et al, 2002).
The FOG Proteins in the Testis: Friend or Foe?— In the mouse testis, Fog1 and Fog2 are coexpressed with Gata1/4/6 in Sertoli and Leydig cells during development (Ketola et al, 2002; Robert et al, 2002). Fog1 is first detected in Sertoli cells on embryonic day 15.5 (E15.5) (Ketola et al, 2002). Testicular Fog1 expression is maintained throughout development but eventually becomes restricted to stage VII–XII tubules (Ketola et al, 2002). In contrast to Fog1, Fog2 can be detected as early as the undifferentiated (bipotential) gonad stage in both sexes (Anttonen et al, 2003). After sex determination, Fog2 expression is maintained in the ovary but is rapidly down-regulated in the testis, so that by E17.5 only the testis capsule and Leydig cells show any significant Fog2 expression (Ketola et al, 2002). Abundant Fog2 expression then reinitiates after birth, and like Fog1, eventually becomes restricted to stage VII–XI tubules in the adult testis (Ketola et al, 2002).
Although the FOG proteins do not bind directly to DNA, in vitro studies indicate that they function as either enhancers or repressors of GATA transcriptional activity depending on the cell and promoter context being studied (Tsang et al, 1997; Fox et al, 1999; Holmes et al, 1999; Lu et al, 1999; Svensson et al, 1999, 2000a; Tevosian et al, 1999). Therefore, it has been suggested that the FOG proteins act as bridging molecules that link GATA proteins with other transcriptional regulators involved in either activation or repression. On GATA-dependent gonadal promoters, however, recent in vitro data have shown the FOG proteins to play a purely repressive role (Robert et al, 2002). The repressive nature of FOG proteins is due in part to their association with the potent transcriptional corepressor C-terminal binding protein-2 (CtBP-2) (Turner and Crossley, 1998; Holmes et al, 1999; Svensson et al, 2000a). Recently, a non–CtBP-2-dependent repression domain has also been identified in the N-terminal regions of the FOG proteins (Svensson et al, 2000a). Thus, FOG repression is likely an important mechanism for modulating the transcription of GATA-dependent genes in the testis in vivo. Indeed, targeted inactivation of the Fog2 gene in the mouse leads to a block in testis development and the absence of several testicular markers, including Mis, P450scc, and 3ß-HSD (Tevosian et al, 2002). At present, however, it remains unclear as to whether the lack of testis-specific markers in these animals is the result of a primary defect in Sertoli and/or Leydig cell gene expression or a secondary defect due to a block in Sertoli cell differentiation and/or fetal Leydig cell development.
The abundance of FOG1 and FOG2 in Sertoli cells indicates that these two proteins play a key role in finetuning GATA-dependent gene expression in Sertoli cells. To date, the best-studied GATA target gene in Sertoli cells is MIS (Viger et al, 1998; Tremblay and Viger, 1999, 2001b; Watanabe et al, 2000; Tremblay et al, 2001). Although the sexually dimorphic expression of MIS is largely controlled by Sox9 (Arango et al, 1999), how MIS levels are specifically down-regulated in postnatal Sertoli cells remains unclear. It has been suggested that the FOG proteins may play such a role (Robert et al, 2002). The fact that overexpression of Fog2 in primary Sertoli cell cultures has been shown to markedly decrease Mis promoter activity is consistent with this hypothesis (Tremblay et al, 2001). The sexually dimorphic expression of Fog2 in the fetal mouse gonad has also been recently suggested to play a role in the down-regulation of Mis expression after overt ovarian differentiation (Anttonen et al, 2003).
Role of GATA Phosphorylation in Hormonal Signaling in the Testis.— Testicular gene expression and function is tightly regulated by the pituitary trophic hormones LH and FSH. In response to hormonal signals, gene expression is modulated predominantly through the cAMP-dependent intracellular signaling pathway, leading to activation of protein kinase A (PKA). PKA then translocates to the nucleus and phosphorylates target proteins (Montminy, 1997; Daniel et al, 1998). The best studied target of cAMP/PKA signaling is the transcription factor CREB (cAMP response element [CRE]-binding protein), which binds as a dimer to the 8-bp palindromic sequence CRE found in the regulatory regions of some cAMP-regulated genes (Mayr and Montminy, 2001). In the testis and other steroidogenic tissues, however, the promoters of several cAMP-regulated genes, such as steroidogenic acute regulatory protein (Star), inhibin a (Inha), stem cell factor (Sl), P450c17 (Cyp17), P450scc (Cyp11a1), and aromatase (Cyp19), lack "classical" CRE elements. This suggests that transcription factors, besides CREB, must also be acting as downstream effectors of cAMP signaling. Indeed, GATA4 has recently been identified as a novel target of hormone-induced cAMP/PKA signaling in gonadal cells. In response to cAMP, GATA4 is directly phosphorylated by PKA on a specific serine residue (Ser261) in the zinc finger region of the protein. This amino acid is perfectly conserved between the rat, mouse, human, bovine, rabbit, frog, fish, and chick GATA4 proteins. Phosphorylation of GATA4 allows for synergistic interactions with the C/EBPß transcription factor (Tremblay et al, 2002) and permits recruitment of the CBP transcriptional co-activator (Tremblay and Viger, 2003c). This leads to robust stimulation of transcription from target gonadal promoters such as StAR (Tremblay and Viger, 2003c). To date, two independent phosphorylation sites have been mapped in the GATA4 protein: Ser105, which is a target of the MAP kinase (MAPK) signaling pathway in the heart (Liang et al, 2001), and Ser261 in gonadal cells (Tremblay and Viger, 2003c). Since the GATA4 protein contains two distinct phosphoacceptor sites, differential phosphorylation of GATA4 in response to various signals might constitute an important regulatory mechanism. However, the interrelationship between these two phosphorylation sites for hormone-regulated gonadal gene expression has not yet been documented. Initial in vitro experiments suggest that Ser261, but not Ser105, is essential for the PKA-mediated enhancement of GATA4 transcriptional activity, at least on the StAR promoter (Viger et al, unpublished data). The fact that the Ser261 site alone is crucial for the PKA enhancement of GATA4 transactivation on the StAR promoter does not formally exclude a role for Ser105 phosphorylation on other targets genes or in response to other signals. In fact, gonadal cells do respond to certain stimuli that activate the cAMP pathway but without the involvement of PKA (Richards, 2001). In these cases, activation of MAPK appears to play a predominant role. Therefore, different signaling pathways and kinases might converge on GATA4 to regulate gonadal gene expression and function. Since the recruitment of CBP is a direct consequence of PKA-mediated phosphorylation of GATA4 (Tremblay and Viger, 2003c), and since CBP-mediated acetylation is known to modulate transcription factor activity, the GATA4 protein itself may be acetylated by CBP in response to hormonal stimulation. The fact that a deacetylase inhibitor (trichostatin A) can enhance the transcriptional activity of GATA4 alone or when used in combination with PKA/CBP (Figure 2) indicates that the GATA4 protein is indeed acetylated under basal conditions and that acetylation likely increases in response to hormonal stimulation. Thus, as depicted in Figure 3, GATA factors could very well represent the foundation of a large transcriptional complex (involving other transcription partners, such as SF1, C/EBPß, and the co-activator CBP/p300) that is required for the activation of different sets of genes in response to differing signals, such as hormones, growth factors, and stress signals in the testis and other steroidogenic tissues.
|
|
Conclusion
Five years ago, little was known about the role of GATA factors in the
reproductive system. Initial studies showed that certain GATA family members
were indeed expressed in both the testis and ovary, and our thinking at that
time was that they might be key regulators of a number of gonadal target
genes. Little did we know that GATA factors would turn out to be important
regulators of gonadal gene transcription throughout development. In the
testis, this is particularly true for GATA4, which appears to function as a
"master regulator" of multiple genes involved in both Sertoli and
Leydig cell function. Indeed, in the past few years, the scope of GATA action
in the male has broadened to include early testis development
(Tevosian et al, 2002), male
sex differentiation (Tremblay and Viger,
2003a), and steroidogenesis
(Tremblay and Viger, 2003b).
To date most of our insights have come from the identification of novel
GATA-dependent promoters. In the years to come, further light will undoubtedly
be shed on the role of GATA factors in andrology as selective in vivo GATA
knockout or knockdown techniques are eventually applied to the testis and
other tissues of the male reproductive tract.
Acknowledgments
R.S.V. is holder of the Canada Research Chair in Reproduction and Sex Development.
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