The 25th Volume: Role of the GATA Family of Transcription Factors in Andrology

Understanding how genes get turned on or off is central to the study of biological processes in both health and disease. Several regulatory mechanisms, which can be positive or negative, have been implicated in the control of tissue- and cell-specific gene expression. These include modulation of chromatin structure, DNA methylation, and the regulation of transcription and translation. Transcription factors are nuclear regulatory proteins that bind specific DNA sequences in the 5′ regulatory or promoter regions of target genes. They are involved in both basal and tissue-specific gene expression. There are several classes of transcription factors that have been defined based on similarities in the structure of the respective DNA-binding domains. They include zinc finger, helix-loop-helix, leucine zipper, and homeobox transcription factors. The GATA family of zinc finger transcription factors is named from the consensus nucleotide sequence (A/TGATAA/G) that these factors bind in the promoter regions of target genes. They were originally identified as crucial regulators of heart development and the differentiation of blood and immune cells. GATA expression, however, is not limited to these two systems. Indeed, reproductive tissues such as the testis and ovary are also prominent sites of GATA expression. As few as 5 years ago, the role of GATA factors in reproductive function was uncharted territory. With the recent contributions to the field, the scientific community has come a long way in filling this void. GATA factors have now been implicated in gonadal development, male sex determination and differentiation, and steroidogenesis. This review will provide a brief overview of the vertebrate family of GATA factors and how these factors have affected the field of andrology. 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). . Structure of the vertebrate family of GATA proteins. All 6 vertebrate GATA factors share a conserved DNA-binding domain consisting of 2 zinc fingers (ZnF), a feature that defines this family of transcription factors. The different GATA factors can be divided into 2 subgroups based on amino acid sequence homology and tissue distribution: the hematopoietic subgroup (GATA 1/2/3) and the cardiac subgroup (GATA 4/5/6). Transactivation domains are found in either the N-terminal (N-term) and/or C-terminal (C-term) portions of the different GATA proteins. NLS, nuclear localization signal. 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). 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). 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. 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. The mammalian testis expresses 3 GATA factors: GATA1, GATA4, and GATA6 of the functional importance of GATA proteins in other these factors have as a of regulators of gene expression and GATA1 was the first GATA factor shown to be expressed in the testis (Ito et al, 1993; Yomogida et al, 1994). it is also the GATA factor expression in the testis is known to be by a promoter et al, 1997). In the Gata1 expression is to Sertoli cells of et al, 1994; Viger et al, 1998; Ketola et al, 2002). in the prepubertal where Sertoli cells the protein et al, 1994). however, the of a that by Sertoli cells in and exhibit Gata1 et al, 1994). In addition to Sertoli cells, recent data by et al have that Leydig cells also GATA1 et al, 2002). This was based on data of from Leydig cells and an of Leydig cells et al, 2002). in or data is however, to that GATA1 is expressed in Leydig cells in vivo. expression of the GATA4 transcription factor has been in 3 different and human et al, 1998; Ketola et al, 1999, 2000; McCoard et al, In the mouse and GATA4 is abundantly expressed from the of gonadal development, where it all cell types present with the notable of germ cells et al, 1998; McCoard et al, gonadal differentiation, GATA4 expression is at in the fetal testis in both Sertoli cells and cells et al, 1998; McCoard et al, In the Sertoli cells to Gata4 after but in Gata1 the predominant GATA factor et al, 1998). GATA4 is also abundantly expressed by the Sertoli cell (Heikinheimo et al, 1997; Robert et al, 2002). like Sertoli cells, GATA4 expression in Leydig cells in the developing mouse and testis through to (Ketola et al, 1999; McCoard et al, 2001), and GATA4 is a of several and/or Leydig cell (Ketola et al, 1999; Robert et al, 2002; et al, 2002). In the human GATA4 expression has been in the mouse and with germ cells (Ketola et al, 2000). Unlike the mouse and GATA4 to be a major GATA factor of both fetal and prepubertal human male germ cells (Ketola et al, 2000). with GATA1 and GATA4, GATA6 is the GATA factor shown to have predominant expression in Sertoli cells. In the Gata6 expression with Gata4 in Sertoli cells during fetal and early development et al, 1998; Ketola et al, 1999; Robert et al, 2002). All 3 GATA factors however, are coexpressed in Sertoli cells of the testis et al, 1994; Viger et al, 1998; Ketola et al, 1999; Robert et al, In Gata6 expression to be specific to Sertoli cells, whereas in GATA6 is in both Sertoli and Leydig cells at least in the fetal testis (Ketola et al, 2003). from the has been to the expression of GATA factors in the other tissues that the male reproductive it is the absence of such can be as a lack of expression or a lack of there is at least of GATA expression in the and seminal et al, 2000). mouse and human were shown to both GATA2 and GATA3 et al, 2000). Although other GATA factor was in GATA6 expression was found in the human and cell et al, 2000). The GATA2 gene was also shown to be abundantly transcribed in the cell et al, 2000). The also identified several GATA elements in the human gene suggesting that GATA factors be involved in the regulation of the gene in the The two other sites of GATA expression in the male reproductive system are the Wolffian of the seminal and vasa and the Gata3 expression in the developing of the in was found while the and control of the Gata3 promoter in mice et al, 1997). Although inactivation of the Gata2 in mice leads to (Tsai et al, rescue of the hematopoietic defect revealed an role for Gata2 in development et al, 1998). and the Gata2 seminal vesicles that were to the vasa deferentia et al, 1998). This the to more at Gata2 expression in the developing Consistent with their Gata2 expression in was found to be strongly expressed in the Wolffian the and the which is target genes for GATA2 in the Wolffian have yet be Although gene inactivation experiments have identified crucial roles for GATA factors in early vertebrate development, they have been for the study of their as regulators of tissue-specific gene expression in since 5 of the 6 mice are embryonic This includes the gene in which embryo to testis development (Pevny et al, 1991; Kuo et al, 1997; Molkentin et al, 1997; Morrisey et al, 1998). the role of these factors in the a inactivation or of GATA function is These types of experiments have to be to into the in vivo roles by GATA1 and GATA4 (Tevosian et al, 2002; et al, 2003). As previously mentioned, the Gata4 gene is abundantly expressed in the somatic cell of the developing mouse the of sex Thus, based on its expression GATA4 was to play a central role in sex determination testis This has been recently confirmed in the in which in vivo of of functions with its via an mutation of the Gata4 gene leads to a block in testis development and a of expression of the (Tevosian et al, 2002). Thus, GATA4 to function as an regulator of expression in the developing Although the has yet to be the of multiple GATA regulatory motifs in the and promoters strongly this a knockout of the Gata1 gene and using the promoter to the Gata1 gene in Sertoli cells, et al recently reported the first knockout of a GATA Gata1 were and et al, 2003). The absence of an was to by Gata4 and Gata6 in Sertoli cells, which the loss of A knockout or of GATA activity be to the functional role of GATA factors in Sertoli cells in which overlapping expression of multiple GATA factors a The lack of knockout has not from into the role by GATA factors in the The that GATA factors specific regulatory motifs in the promoter regions of genes has been to novel for these factors in tissues, including the The or promoter was identified as the first known target for GATA4 in Sertoli cells et al, 1998). The is the of testis male sex differentiation by of the precursors of the female reproductive in et al, gene expression is during gonadal lack of expression in humans causes a in which affected exhibit both male and female internal reproductive an of the conserved 5′ regulatory elements of the several transcription factors have been to in such as the nuclear factor and the protein et al, 1994; et al, 1997; et al, 1999). since and are in several tissues that do not other factors act to expression to the gonads. Indeed, between transcription factors has been shown to to tissue-specific expression et al, this includes GATA4 and Viger, 1999; et al, 2000; Tremblay et al, GATA4 has been shown to both the mouse and human promoters through a transcriptional with and Viger, 1999; et al, 2000). Although human GATA4 gene mutations have yet been linked to gonadal recent that of for of human male sex differentiation expression and Viger, The overlapping expression of multiple GATA factors in Sertoli cells is a strong that these GATA factors are key regulators of Sertoli gene expression and function during Indeed, in addition to GATA factors have been shown to several promoters These include the et al, 1998; Ketola et al, 1999; Tremblay and Viger, et al, 2000), and Viger, and 2001), and transcription factor and and et al, In vitro studies by et al have shown that the promoter is activated by GATA1 the of GATA1 and GATA4 in Sertoli cells et al, 2000). since all GATA factors are known to have similar DNA-binding properties and Orkin, based on properties a Sertoli cell gene or not to regulation by a GATA factor on interactions with specific transcriptional partners as either or Sertoli cells, GATA are also prominently expressed in the cell of the testis Although both GATA4 and GATA6 are expressed in cells development (Heikinheimo et al, 1997; Laitinen et al, 2000), in the GATA4 is the predominant GATA factor of both fetal and Leydig cells et al, 1998; Ketola et al, 1999, 2000). Thus, GATA factors, and in GATA4, have been to be key regulators of in the testis and Viger, In of this the promoters of several genes have been reported to contain or more consensus GATA regulatory motifs and Viger, in vitro several have confirmed that of these promoters are for GATA factors. studied to include the promoters for and Viger, et al, Tremblay and Viger, regulatory protein et al, 1999; and 2000; Tremblay and Viger, Tremblay et al, 2002), and 2 Viger et al, In addition to their ability to directly transcription of target GATA factors also to the tissue-specific activity and of of these promoters via interactions with the nuclear and the binding protein and Viger, Although the list of target genes for GATA factors in cells to is known how GATA expression is in the et al that Sertoli cell expression of Gata1 is in germ mouse suggesting that GATA1 expression in the testis is by or more factors by germ cells. The of a of GATA1 in the testis has recently with the that Gata1 expression in both Leydig cells and Sertoli cell is by et al, 2002). Interestingly, the was specific for cells, since Gata1 expression in erythroid cells was similar however, the physiological significance of this regulation In to GATA1, and/or have been shown to Gata4 and/or Gata6 expression in several gonadal cell including Sertoli cells and Leydig cells (Heikinheimo et al, 1997; Ketola et al, 1999). In the role of in the regulation of GATA4 is at least in the by the of an mutation of the with GATA4 expression et al, 2002). In the mouse Fog1 and Fog2 are coexpressed with in Sertoli and Leydig cells during development (Ketola et al, 2002; Robert et al, 2002). Fog1 is first in Sertoli cells on embryonic (Ketola et al, 2002). Fog1 expression is development but to (Ketola et al, 2002). In to Fog2 can be as early as the gonad in both et al, 2003). sex Fog2 expression is in the ovary but is in the that by the testis and Leydig cells Fog2 expression (Ketola et al, 2002). Fog2 expression after and like to in the testis (Ketola et al, 2002). Although the FOG proteins do not bind directly to DNA, in vitro studies 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). it has been that the FOG proteins act as that GATA proteins with other transcriptional regulators involved in either or GATA-dependent gonadal however, recent in vitro data have shown the FOG proteins to play a role et al, 2002). The of FOG proteins is in to their with the transcriptional C-terminal binding and 1998; Holmes et al, 1999; Svensson et al, a domain has also been identified in the N-terminal regions of the FOG proteins (Svensson et al, Thus, FOG is an for modulating the transcription of GATA-dependent genes in the testis in vivo. Indeed, inactivation of the Fog2 gene in the mouse leads to a block in testis development and the absence of several including and (Tevosian et al, 2002). however, it as to the lack of in these is the result of a defect in Sertoli and/or Leydig cell gene expression or a defect to a block in Sertoli cell differentiation and/or fetal Leydig cell development. The of FOG1 and FOG2 in Sertoli cells that these two proteins play a key role in GATA-dependent gene expression in Sertoli cells. the GATA target gene in Sertoli cells is et al, 1998; Tremblay and Viger, 1999, et al, 2000; Tremblay et al, Although the expression of is by et al, how are specifically in Sertoli cells has been that the FOG proteins play such a role et al, 2002). The that of Fog2 in Sertoli cell has been shown to promoter activity is with this et al, The expression of Fog2 in the fetal mouse gonad has also been recently to play a role in the of expression after differentiation et al, 2003). gene expression and function is by the and In to gene expression is through the to of protein A to the and target proteins 1997; et al, 1998). The studied target of is the transcription factor which as a to the sequence found in the regulatory regions of genes and In the testis and other tissues, however, the promoters of several such as regulatory protein a cell factor and lack This that transcription factors, also be as of Indeed, GATA4 has recently been identified as a novel target of in gonadal cells. In to GATA4 is directly by on a specific in the zinc finger of the This amino acid is conserved between the and GATA4 proteins. of GATA4 for interactions with the transcription factor et al, and of the transcriptional and Viger, This leads to of transcription from target gonadal promoters such as and Viger, two sites have been in the GATA4 which is a target of the in the heart et al, 2001), and in gonadal cells and Viger, Since the GATA4 protein two distinct of GATA4 in to an regulatory the between these two sites for gonadal gene expression has not yet been in vitro experiments that but not is for the of GATA4 transcriptional at least on the promoter et al, The that the is crucial for the of GATA4 on the promoter does not a role for on other genes or in to other In gonadal cells do to that the but the of In these of to play a predominant different and on GATA4 to gonadal gene expression and Since the of is a of of GATA4 and Viger, and since is known to transcription factor the GATA4 protein be by in to The that a can the transcriptional activity of GATA4 or in with (Figure that the GATA4 protein is basal and that in to Thus, as in GATA factors very well the of a transcriptional other transcription such as and the that is required for the of different of genes in to such as growth factors, and in the testis and other tissues. . of activity the transcriptional between GATA4 and cells were with the promoter with an expression or expression for GATA4, or different of the 3 factors in the absence or of of the A are shown as control The of the or transcriptional by that GATA4 be a target for . for GATA factors as of in cells. In the Sertoli and Leydig cell gene expression and function are by the and binding to cell to the regulatory of protein A of the and its to the where it target proteins. In both Sertoli and Leydig cells, GATA factors are novel for As of GATA4 at for an with multiple transcriptional partners and the of the The result is expression of GATA-dependent target genes such as regulatory protein and years ago, was known the role of GATA factors in the reproductive studies that GATA family members were expressed in both the testis and and at that was that they be key regulators of a of gonadal target genes. that GATA factors to be regulators of gonadal gene transcription development. In the this is for GATA4, which to function as a of multiple genes involved in both Sertoli and Leydig cell Indeed, in the few the of GATA action in the male has to include early testis development (Tevosian et al, 2002), male sex differentiation and Viger, and and Viger, most of have come from the of novel GATA-dependent In the years to further will be on the role of GATA factors in as in vivo GATA knockout or are to the testis and other tissues of the male reproductive is of the in and

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