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 et al, 2000), and GATA4 mutations with congenital heart defects (Garg et al, 2003). All vertebrate GATA proteins contain a conserved DNA-binding domain of two zinc The C-terminal zinc finger is required for and DNA-binding to the GATA the N-terminal zinc finger to the and of the DNA-binding and Orkin, 1990; and 1992; et al, Since members of the GATA family share a conserved DNA-binding exhibit similar DNA-binding and 1993; and Orkin, This however, with their specific roles in vivo (Pevny et al, 1991; et al, 1994; et al, 1995; Pandolfi et al, 1995; et al, 1997; Molkentin et al, 2000; Morrisey et al, 1998; Zhou et al, 1998; Koutsourakis et al, 1999; et al, 2000). The of GATA is in with other transcriptional and Nemer, 1999; Molkentin, 2000). Indeed, is now extensive of expressed or factors that are to with GATA factors to control tissue-specific transcription in the hematopoietic the heart, the pituitary, the and the gonads et al, 1995; and Orkin, 1995; et al, 1995; et al, 1996; et al, 1997; Gordon et al, 1997; Lee et al, 1998; et al, 1998; et al, 1999; and 1999; et al, 2000; et al, 2000; et al, 2002; et al, 2003). the different the are the zinc finger proteins of GATA1 and of GATA2 because the proteins were originally identified as their to with the N-terminal zinc fingers of the different GATA factors et al, 1997; et al, 1999; et al, 1999; et al, 1999; et al, 1999). Like GATA1, is expressed in hematopoietic cell lineages et al, 1997). Similarly, is with GATA4 in the heart, brain, and gonads et al, 1999; et al, 1999; et al, 2000; Ketola et al, 2002; Robert et al, 2002; et al, 2003). knockout studies have revealed that their GATA have crucial developmental in the lack of to a in erythroid and differentiation et al, 1998), of to defects in heart and development et al, et al, 2000; et al, as as development et al, Although the proteins not to bind to as either or of GATA transcriptional on the cell and promoter et al, 1997; et al, 1999; et al, 1999; et al, 1999; et al, et al, 1999; Robert et al, The role of proteins in transcription in the testis will be As GATA factors are not to the hematopoietic and cardiac but are expressed in a of This tissues of both the male and female reproductive with the sites of expression the testis and DNA-binding proteins are found in the gonads of from to et al, 1991; Tamura et al, 1993; et al, 1994; Laverriere et al, 1994; et al, 1994; et al, 1994; and 1995; Heikinheimo et al, 1997; Viger et al, 1998; Ketola et al, 1999; et al, 2000), that a functional role for GATA factors in the gonads has been conserved during the 6 vertebrate GATA are expressed in the GATA1 et al, 1993; et al, 1994; Viger et al, 1998), GATA2 et al, GATA4 et al, 1997; Viger et al, 1998; Ketola et al, 1999; et al, and GATA6 et al, 1997; Ketola et al, 1999; Robert et al, As a GATA factors the cell of the The are which is expressed specifically in cells of the mouse ovary during a of early development et al, and in addition to cells, has also been to be expressed in and cells of the human testis et al, 2000). The of GATA expression in cells, however, has to be The testis GATA GATA1, 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 et al, 1993; et al, 1994). it is also the GATA factor expression in the testis is 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, in the 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, This was based on data of from Leydig cells and of Leydig cells et al, in or data is however, to that GATA1 is expressed in Leydig cells in expression of the GATA4 transcription factor has been in different and human et al, 1998; Ketola et al, 2000; et al, In the mouse and GATA4 is abundantly expressed from the of gonadal development, where it cell present with the of cells et al, 1998; et al, gonadal differentiation, GATA4 expression is in the testis in both Sertoli cells and cells et al, 1998; et al, In the Sertoli cells to Gata4 after but in Gata1 the GATA factor et al, 1998). GATA4 is also abundantly expressed by the Sertoli cell et al, 1997; Robert et al, Sertoli cells, GATA4 expression in Leydig cells in the developing mouse and testis to et al, 1999; et al, and GATA4 is a of several and/or Leydig cell et al, 1999; Robert et al, 2002; et al, In the human GATA4 expression has been in the mouse and with cells et al, 2000). Unlike the mouse and GATA4 to be a GATA factor of both and human male cells et al, 2000). with GATA1 and GATA6 is the GATA factor shown to have expression in Sertoli cells. In the Gata6 expression with Gata4 in Sertoli cells during and early development et al, 1998; Ketola et al, 1999; Robert et al, All GATA factors however, are 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, in GATA6 is in both Sertoli and Leydig cells in the testis 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 is 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 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 the and control of the Gata3 promoter in mice et al, 1997). Although inactivation of the Gata2 in mice to (Tsai et al, rescue of the hematopoietic defect revealed 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 Gata2 expression in the developing Consistent with their Gata2 expression in was found to be expressed in the Wolffian the and the which is target genes for GATA2 in the Wolffian have be Although gene inactivation experiments have identified crucial roles for GATA factors in early vertebrate development, have been for the study of their as regulators of tissue-specific gene expression in since 5 of the 6 mice are embryonic This the gene in which embryo to testis development (Pevny et al, 1991; 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 of experiments have to be to into the in vivo roles by GATA1 and GATA4 et al, 2002; et al, 2003). As the Gata4 gene is abundantly expressed in the cell of the developing mouse the of sex 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 with its mutation of the Gata4 gene to a in testis development and a of expression of the et al, GATA4 to function as regulator of expression in the developing Although the has to be the of multiple GATA regulatory motifs in the and promoters this a knockout of the Gata1 gene and using the promoter to the Gata1 gene in Sertoli cells, et al recently the first knockout of a GATA Gata1 were and et al, 2003). The absence of was to by Gata4 and Gata6 in Sertoli cells, which the loss of A knockout or of GATA 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 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 causes a in which affected exhibit both male and female internal reproductive 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 not other factors to expression to the Indeed, between transcription factors has been shown to to tissue-specific expression et al, this GATA4 and 1999; et al, 2000; et al, GATA4 has been shown to both the mouse and human promoters a transcriptional with and 1999; et al, 2000). Although human GATA4 gene mutations have been linked to gonadal recent that of for of human male sex differentiation expression and 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; and et al, 2000), and and 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 GATA factors are to have similar DNA-binding and Orkin, based on a Sertoli cell gene or not to regulation by a GATA factor on with specific transcriptional 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 et al, 1997; et al, 2000), in the GATA4 is the GATA factor of both and Leydig cells et al, 1998; Ketola et al, 2000). GATA and in have been to be key regulators of in the testis and In of this the promoters of several genes have been to contain or more consensus GATA regulatory motifs and in vitro several have confirmed that of these promoters are for GATA factors. to include the promoters for and et al, and regulatory protein et al, 1999; and 2000; and et al, and 2 Viger et al, In addition to their to transcription of target GATA factors also to the tissue-specific and of of these promoters with the nuclear and the binding protein and Although the of target genes for GATA factors in cells to is how GATA expression is in the et al that Sertoli cell expression of Gata1 is in mouse that GATA1 expression in the testis is by or more factors by 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, Interestingly, the was specific for cells, since Gata1 expression in erythroid cells was similar however, the physiological 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 et al, 1997; Ketola et al, 1999). In the role of in the regulation of GATA4 is in the by the of mutation of the with GATA4 expression et al, In the mouse and are with in Sertoli and Leydig cells during development et al, 2002; Robert et al, is first in Sertoli cells on embryonic et al, expression is development but to et al, In to can be as early as the in both et al, 2003). sex expression is in the ovary but is in the that by the testis and Leydig cells expression et al, expression after and to in the testis et al, Although the proteins not bind to in vitro studies that function as either or of GATA transcriptional on the cell and promoter et al, 1997; et al, 1999; et al, 1999; et al, 1999; et al, et al, 1999). it has been that the proteins as that GATA proteins with other transcriptional regulators involved in either or gonadal however, recent in vitro data have shown the proteins to play a role et al, The of proteins is in to their with the transcriptional C-terminal binding and 1998; et al, 1999; et al, a domain has also been identified in the N-terminal regions of the proteins et al, is for the transcription of genes in the testis in Indeed, inactivation of the gene in the mouse to a in testis development and the absence of several including and et al, 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 in Sertoli cell differentiation and/or Leydig cell development. The of and in Sertoli cells that these two proteins play a key role in gene expression in Sertoli cells. the GATA target gene in Sertoli cells is et al, 1998; and et al, 2000; et al, Although the expression of is by et al, how are specifically in Sertoli cells has been that the proteins play such a role et al, The that of in Sertoli cell has been shown to promoter is with this et al, The expression of in the mouse 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 the to of protein A to the and target proteins 1997; et al, 1998). The 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 also be as of Indeed, GATA4 has recently been identified as a novel target of in gonadal cells. In to GATA4 is by on a specific in the zinc finger of the This amino acid is conserved between the and GATA4 proteins. of GATA4 for with the transcription factor et al, and of the transcriptional and This to of transcription from target gonadal promoters such as and two sites have been in the GATA4 which is a target of the in the heart et al, and in gonadal cells and Since the GATA4 protein two distinct of GATA4 in to regulatory the between these two sites for gonadal gene expression has not been in vitro experiments that but not is for the of GATA4 transcriptional 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 to that the but the of In these of to play a different and on GATA4 to gonadal gene expression and Since the of is a of of GATA4 and and since is to transcription factor the GATA4 protein be by in to The that a can the transcriptional of GATA4 or in with (Figure that the GATA4 protein is basal and that in to as in GATA factors the of a transcriptional other transcription such as and the that is required for the of different of genes in to such as growth and in the testis and other . of the transcriptional between GATA4 and cells were with the promoter with expression or expression for or different of the 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 for with multiple transcriptional and the of the The result is expression of target genes such as regulatory protein and years ago, was the role of GATA factors in the reproductive studies that GATA family members were expressed in both the testis and and that was that 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 which to function as a of multiple genes involved in both Sertoli and Leydig cell Indeed, in the few the of GATA in the male has to include early testis development et al, male sex differentiation and and and of have come from the of novel 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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