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University of Illinois at Chicago Department of Physiology and Biophysics Chicago, Illinois 60612-7342
Address all correspondence and requests for reprints to: Dale B. Hales, Ph.D., University of Illinois at Chicago, Department of Physiology and Biophysics, 835 South Walcott Avenue, Room E202, Chicago, Illinois 60612-7342. E-mail: dbhale{at}uic.edu
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Introduction |
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 Top Introduction References |
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Members of the GATA-binding protein family of transcription factors recognize the consensus DNA sequence (T/A)GATA(A/G), named the GATA motif, an essential cis element present in the promoter region of numerous genes. GATA proteins, which recognize and bind to this motif, are widely expressed and the evolutionary conservation indicates the importance of these factors as transcriptional regulators, playing a significant role in development and differentiation. To date, six vertebrae GATA factors have been identified and can be divided into two subgroups based on homology and tissue distribution. GATA 1/2/3 comprise the "hematopoietic group" and GATA 4/5/6 comprise the "cardiac group." GATA factors are zinc-finger proteins, and all six exhibit similar DNA-binding properties. GATA factors have distinct developmental expression patterns and play essential and nonoverlapping roles. The functional specificity of different GATA factors is mediated, in part, via protein interactions with other factors. Three of the six GATA factors, GATA-1, GATA-4, and GATA-6 are expressed in the mammalian testis and ovary. GATA factors appear to be key regulators of Sertoli cell-specific gene expression during development. It is now evident that GATA-4 is an important factor in the cascade of regulators that control gonadal development and sex differentiation in mammals. Abundant GATA-4 expression is maintained in Sertoli cells throughout embryonic development but is markedly down-regulated shortly after the histological differentiation of the ovary on embryonic day 13.5. This pattern of expression suggests that GATA-4 might be involved in early gonadal development and possibly sexual dimorphism. Indeed, consistent with this hypothesis, Viger et al. (3) found that the Muüllerian-inhibiting substance (MIS) promoter harbors a conserved GATA element and is a downstream target for GATA-4. The expression pattern of MIS is tightly regulated in fetal, neonatal, and prepubertal testes and adult ovaries and is well conserved among mammalian species. GATA-4 and SF-1 are important in the regulation of MIS expression. Multiple SF-1- and GATA-4-binding sites in the MIS promoter are required for its normal tissue-specific and developmental expression (4).
The role of GATA-4 in the development and function of murine gonads has been well established. Recently, the importance of GATA-4 in human gonadal development was confirmed. GATA-4 was shown to be expressed from early human fetal testicular development to adulthood. This transcription factor is evident in Sertoli cells through fetal and postnatal development. In Leydig cells, GATA-4 is expressed during the fetal period and after puberty, coinciding with the periods of active androgen synthesis in the testis; thus suggesting a link between GATA-4 and steroidogenesis (5). Indeed, GATA-4 has been identified as a critical regulatory factor for the expression of steroidogenic acute regulatory protein (StAR) (6, 7)
Both GATA-1 and GATA-4 have been shown to transcriptionally regulate
the expression of the inhibin/activin subunit genes. Recent analysis of
the role of GATA-1 and GATA-4 in the regulation of the
-inhibin/activin subunit promoter indicated that both factors
transactivate the promoter in testicular cells via complicated,
interacting mechanisms (8). Previously, the role of GATA
factors in the regulation of the 
-subunit gene in the testes had
been established by these same investigators. The basal transcription
of inhibin -subunit gene in testicular MA-10 cells was up-regulated
by testicular GATA-1 but not GATA-4 through its interaction with the
GATA binding site, providing further evidence of the functional role of
GATA-binding proteins in the regulation of testicular gene expression
(9).
GATA factors have also been implicated as tissue-specific regulatory factors in the ovary. GATA-4 and GATA-6 mRNA and GATA-4 protein are present in granulosa and theca cells in both preantral and antral follicles in rodents and humans, supporting their role in the regulation of ovarian development and function (10). GATA-4 was shown to participate in the regulation of StAR gene expression in rat ovarian granulosa cells (6).
Mechanisms controlling aromatase gene expression are complicated by the existence of multiple tissue-specific promoters. The most proximally located PII promoter is mainly active in ovarian granulosa cells. Recently, a novel DNA binding element in the aromatase promoter was identified and characterized. It is 100% conserved between humans and rodents and functions in both an orientation- and promoter-independent manner. The core region of this element contains two consensus binding sites for members of the GATA transcription factors. The authors suggest that the expression of GATA-4, and more importantly, other yet to be identified GATA or GATA-related factor(s), are important in the control of aromatase gene expression (11).
Important new insight into the importance of GATA factors in the
gonadal-specific control of gene expression is gleaned from Tremblay
and Viger’s article, which appears in this issue of
Endocrinology (12). The authors provide a
detailed overview of the current knowledge about GATA factors and then
examine the role of GATA-4 in the regulation of five gonadal-specific
genes: StAR, aromatase, inhibin, MIS, and SF-1. Several studies,
including those cited herein, have examined the role of GATA factors in
the regulation of gonadal target genes. What distinguishes this elegant
study is the investigator’s simultaneous examination of five putative
GATA targets in a side-by-side comparison. This study is also unique in
its examination of the role of GATA-4 in regulating SF-1 expression.
Consistent with most GATA-dependent promoters described thus far, the
conserved GATA motifs in the five gonadal promoters examined in this
study were located in close proximity to the start site of
transcription. The authors focused on GATA-4 because it is the sole
GATA family member that is expressed in all gonadal cell types
(Sertoli, granulosa, theca, and Leydig) where these promoters are
normally active. The interaction of exogenously and endogenously
expressed GATA-4 with these promoters was confirmed by gel-shift
analysis. To assess the functional interaction of GATA-4 with these
promoters, reporter constructs were transfected into CV-1 cells, a
heterologous cell line that does not express GATA factors. Despite the
formation of DNA-protein complexes, the gonadal promoters were
differentially regulated by GATA-4. MIS and inhibin- were modestly
up-regulated, StAR and the PII aromatase reporters were strongly
activated, but the SF-1 promoter was not. The specificity of this
regulation was confirmed by deletion analysis, which led the authors to
conclude the promoter context (i.e. cell type) plays an
important role in how GATA-containing gonadal promoters respond to
exogenously expressed GATA factors.
Each of the gonadal promoters contains SF-1 binding sites, in addition to GATA binding motifs. This theme is common to most gonadal-specific promoters, in addition to the five analyzed in this study. This observation, coupled with the author’s previous demonstration that SF-1 and GATA-4 synergistically activate the MIS promoter (3) prompted them to test whether SF-1/GATA-4 synergism contributes to the transcription of the other promoters. They show that in addition to MIS, the aromatase and inhibin promoters, but not SF-1 or StAR promoters exhibited synergistic activation by SF-1 and GATA-4. They conclude that transcriptional synergism constitutes another aspect of the differential activation of gonadal genes by GATA-4.
The role of SF-1 at many levels of the reproductive and adrenal axes is
well established, and considerable work has focused on elucidating its
role. However, the transcriptional mechanisms that control its temporal
and tissue-specific expression warrant further investigation. The
coincident expression of GATA factors and SF-1 may suggest a functional
relationship between these transcription factors. To explore this
relationship, the authors determined that the proximal SF-1 promoters
of the mouse, rat, and human genes all contained a conserved, and
previously uncharacterized, GATA binding motif. Gel shift studies
demonstrated that highaffinity, specific DNA-protein complexes
were formed at these sequences with recombinant GATA-4. The functional
analysis, however, indicated that other cell-specific factors are
required to drive transcription of the SF-1 gene because there was no
activation of the reporter construct in the heterologous CV-1 cells. To
determine if other GATA factors other than GATA-4 were active, the
authors tested GATA-1 and GATA-6, both known to be expressed in the
gonads, but neither were active in CV-1 cells. These data suggested
that other additional factors not expressed in CV-1 cells were
required, so an analysis of GATA-4 transactivation in other cell types
was performed. Of the various cell lines tested, GATA-4 caused a
significant activation of SF-1 in T3 and MSC cells. These results
were extended by analysis of synthetic oligonucleotide reporters that
contained only the GATA element from the SF-1 gene. This experiment
demonstrated that the SF-1 GATA element is functional when taken out of
its natural promoter context. The cell-specific activation of SF-1 by
GATA-4 indicated that other transcription factors endogenously
expressed in these cells are required for promoter activity. A cursory
analysis of other factors known to be coexpressed with SF-1 was unable
to determine the identity of these cell-specific factors. This
experiment, however, provides the groundwork for subsequent work, to
identify the other players involved in the gonadal-specific activation
of SF-1 by GATA-4.
Gel shift analysis, such as reported in this work, is useful in revealing DNA-protein interactions but cannot determine if these interactions are functional. The transactivation activity of most transcription factors is modulated, or controlled by posttranslational events—either covalent modifications such as phosphorylation, or by protein-protein interactions. Little is known about this higher order regulation of GATA factors. The intriguing results presented by Tremblay and Viger (12) offer us new insight into the control of GATA factor activity. The authors present the results of an experiment where they truncate the entire N-terminal region of GATA-4 and assess its ability to transcriptionally regulate SF-1. Interestingly, the truncated form of GATA-4 was able to significantly activate the SF-1 reporter in CV-1 cells. This observation suggests that GATA-4 activity and the ability to confer tissue-specific control are regulated by posttranslational modification of the amino-terminal region of the protein, or by association with other proteins expressed in a cell-specific manner—or perhaps a combination of both. Certainly this finding will provide the investigators a wealth of possibilities to explore.
The authors suggest that their demonstration that GATA-4, in the correct cellular context, conveys tissuespecific expression to the five gonadal promoters is a mechanism shared by many systems—where a single factor controls multiple target genes. It will be important to determine if GATA-4 participates in the gonadal-specific expression of the murine Cyp17 gene—arguable the most highly selective and gonadal-specific promoter. Indeed, transfactor database analysis reveals several consensus GATA binding sites in the promoters of CYP17 gene from different species, including the mouse where Cyp17 expression is exclusive to the ovary and testis.
The authors conclude that GATA is a pan-gonadal factor but that it requires the participation of yet unidentified coregulators, and/or activities, to control SF-1 expression. A theme common to most studies that examine the role of GATA factors in the regulation of gonadal-specific expression of target genes is an examination of the concomitant involvement of SF-1. Tremblay and Viger’s study is the first to examine the control of SF-1 transcription in the context of gonad-specific gene expression. Their conclusion that cross-talk between GATA-4 and SF-1 may be an important mechanism for ensuring the proper spatiotemporal expression of crucial factors during development is supported by their study, but it needs to be critically and more extensively evaluated.
Received December 29, 2000.
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References |
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TopIntroductionReferences |
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and GATA-4 binding regions within
the promoter of the steroidogenic acute regulatory protein (StAR) gene
are required for transcription in rat ovarian cells. J Biol Chem 274:17987–17996This article has been cited by other articles:
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  S. Lee, Q. Sha, X. Wu, G. Calenda, and J. Peng Expression Profiles of Mouse Kell, XK, and XPLAC mRNA J. Histochem. Cytochem., April 1, 2007; 55(4): 365 - 374. [Abstract] [Full Text] [PDF]
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 B. Ritz-Laser, A. Mamin, T. Brun, I. Avril, V. M. Schwitzgebel, and J. Philippe The Zinc Finger-Containing Transcription Factor Gata-4 Is Expressed in the Developing Endocrine Pancreas and Activates Glucagon Gene Expression Mol. Endocrinol., March 1, 2005; 19(3): 759 - 770. [Abstract] [Full Text] [PDF]
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 H. A. LaVoie The Role of GATA in Mammalian Reproduction Experimental Biology and Medicine, December 1, 2003; 228(11): 1282 - 1290. [Abstract] [Full Text] [PDF]
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 F. Lindeboom, N. Gillemans, A. Karis, M. Jaegle, D. Meijer, F. Grosveld, and S. Philipsen A tissue-specific knockout reveals that Gata1 is not essential for Sertoli cell function in the mouse Nucleic Acids Res., September 15, 2003; 31(18): 5405 - 5412. [Abstract] [Full Text] [PDF]
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 M. Bielinska, H. Parviainen, S. B. Porter-Tinge, S. Kiiveri, E. Genova, N. Rahman, I. T. Huhtaniemi, L. J. Muglia, M. Heikinheimo, and D. B. Wilson Mouse Strain Susceptibility to Gonadectomy-Induced Adrenocortical Tumor Formation Correlates with the Expression of GATA-4 and Luteinizing Hormone Receptor Endocrinology, September 1, 2003; 144(9): 4123 - 4133. [Abstract] [Full Text] [PDF]
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 J. J. Tremblay and R. S. Viger Transcription Factor GATA-4 Is Activated by Phosphorylation of Serine 261 via the cAMP/Protein Kinase A Signaling Pathway in Gonadal Cells J. Biol. Chem., June 6, 2003; 278(24): 22128 - 22135. [Abstract] [Full Text] [PDF]
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 I. Ketola, J. Toppari, T. Vaskivuo, R. Herva, J. S. Tapanainen, and M. Heikinheimo Transcription Factor GATA-6, Cell Proliferation, Apoptosis, and Apoptosis-Related Proteins Bcl-2 and Bax in Human Fetal Testis J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1858 - 1865. [Abstract] [Full Text] [PDF]
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S. Basciani, S. Mariani, M. Arizzi, S. Ulisse, N. Rucci, E. A. Jannini, C. D. Rocca, A. Manicone, C. Carani, G. Spera, et al. Expression of Platelet-Derived Growth Factor-A (PDGF-A), PDGF-B, and PDGF Receptor-{alpha} and -{beta} during Human Testicular Development and Disease J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2310 - 2319. [Abstract] [Full Text] [PDF]
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 S. G. Tevosian, K. H. Albrecht, J. D. Crispino, Y. Fujiwara, E. M. Eicher, and S. H. Orkin Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2 Development, January 10, 2002; 129(19): 4627 - 4634. [Abstract] [Full Text] [PDF]
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