Editorial: Gonadal-Specific Transcription Factors-GATA (Go) 4 It!

Since the identification of steroidogenic factor 1 (SF-1 or ADBP-1) as a factor involved in the regulation of steroidogenic enzyme gene expression, and embryological development of the gonads, much research has focused on the role of SF-1 as a gonadal-specific factor. While initially cloned as a transcriptional regulator of the various steroidogenic enzyme genes, it has become clear through genetic ablation experiments that SF-1 is an essential factor in adrenal and gonadal development and for the proper functioning of the hypothalamic-pituitary-gonadal axis. These SF-1 knockout mice exhibited adrenal and gonadal agenesis, male-to-female sex reversal of their internal and external genitalia, and death from adrenocortical insufficiency. These findings showed unequivocally that SF-1 is essential for the embryonic survival of the primary steroidogenic organs. SF-1 knockout mice also had impaired pituitary expression of gonadotropins and agenesis of the ventromedial hypothalamic nucleus, establishing that SF-1 regulates reproductive function at all three levels of the hypothalamic-pituitary gonadal axis (for recent reviews, see Refs. 1 and 2). However, while SF-1 is clearly important in the regulation of steroidogenic enzymes and essential for development of the reproductive axes, SF-1 is not a gonadal-specific regulatory factor. Members of the GATA family of transcription factors, on the other hand, are emerging as some of the most important gonadal-specific regulatory factors. 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 Muüllerianinhibiting 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-1and 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 b-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 a-subunit gene in the testes had been established by these same investigators. The basal transcription of inhibin a-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 Received December 29, 2000. 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@uic.edu. 0013-7227/01/$03.00/0 Vol. 142, No. 3 Endocrinology Printed in U.S.A. Copyright © 2001 by The Endocrine Society