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GATA Transcription Factors in the Developing Reproductive System Tamara Zaytouni, Evgeni E. Efimenko, and Sergei G. Tevosian1 Department of Genetics, Dartmouth Medical School, Hanover, NH, USA

I. Introduction A. Gonadal development in mammals B. Testis determination and differentiation C. Ovarian determination and differentiation D. Germ cell development II. Molecular Control of Gonadal Development III. Canonical WNT Signaling Control of Gonadal Development IV. The GATA–FOG Transcriptional Partnership V. GATA4–FOG2 Control of Gonadal Development A. Gonadal expression of GATA and FOG proteins B. The role of GATA and FOG proteins in sex determination and early gonadal development C. Differential regulation of target genes by GATA4–FOG2 complex and canonical WNT signaling in the ovary D. Conditional targeting reveals additional roles for GATA4/FOG2 proteins in gonadal development E. Role of GATA4 and FOG2 proteins in Leydig cells F. GATA factors in postnatal ovary and differentiated ovarian cells VI. Conclusions Acknowledgment References

1 Current address: Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA

Advances in Genetics, Vol. 76 Copyright 2011, Elsevier Inc. All rights reserved.

0065-2660/11 $35.00 DOI: 10.1016/B978-0-12-386481-9.00004-3

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ABSTRACT Previous work has firmly established the role for both GATA4 and FOG2 in the initial global commitment to sexual fate, but their (joint or individual) function in subsequent steps remained unknown. Hence, gonad-specific deletions of these genes in mice were required to reveal their roles in sexual development and gene regulation. The development of tissue-specific Cre lines allowed for substantial advances in the understanding of the function of GATA proteins in sex determination, gonadal differentiation and reproductive development in mice. Here we summarize the recent work that examined the requirement of GATA4 and FOG2 proteins at several critical stages in testis and ovarian differentiation. We also discuss the molecular mechanisms involved in this regulation through the control of Dmrt1 gene expression in the testis and the canonical Wnt/ß-catenin pathway in the ovary. ß 2011, Elsevier Inc.

I. INTRODUCTION A. Gonadal development in mammals The term “sex” is commonly applied to either of two complementary groups of organisms (e.g., males and females) that join their genetic material in order to reproduce in the process referred to as sexual reproduction. The propagation of all vertebrate species is contingent on the proper development of reproductive organs that are able to support the differentiation of germ cells into two types of gametes: sperm and eggs that carry the genetic material. Sex in eutherian mammals is determined genetically by the inheritance, at conception, of the Y chromosome by males but not females. Primary sex determination begins when a bipotential (or indifferent) gonadal primordium makes a fate decision resulting in its differentiation into a male/testis or a female/ovary gonad (Fig. 4.1). The initiation of the testis pathway depends on gonadal expression of the Y-linked gene, Sry (Gubbay et al., 1990; Koopman et al., 1991). Once SRY expression begins, expression patterns of other genes in the gonad begin to diverge. The two alternative sex fates are thought to emerge through antagonistic activities of sexspecific transcription factors in a restricted number of gonadal somatic cells; this initial cell fate decision is further expanded in the rest of the gonad by extracellular non-cell-autonomous signals that promote one developmental program while suppressing the other (reviewed in Maatouk and Capel, 2008; Swain and Lovell-Badge, 1999; Wilhelm et al., 2007). The testis initiates its organization earlier in development to form morphologically distinguishing structures known as seminiferous tubules in which somatic Sertoli cells surround clusters of germ cells that differentiate asynchronously to provide a constant supply of mature

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Adult

Coelomic vessel

Cortex Medulla

Primordial germ cell Germ cell Meiotic germ cell Somatic cell progenitor Granulosa Peritubular myoid cell Sertoli cell Fetal Leydig cell Adult Leydig cell Theca cell Vasculature

Primordial follicle Primary follicle Activated primary follicle Antral follicle

Figure 4.1. A diagram representing mouse gonad morphogenesis. At E11.5, the bipotential gonad harbors progenitors for both somatic and germ cells. Sex determination events result in the differentiation of the somatic progenitors in the bipotential gonad toward the testis or ovary fate. Embryonic development of the testis is characterized by the formation of testis cords, the coelomic arterial vessel, and Leydig cells by E13.5. Ovarian development includes entry of germ cells into meiosis at E13.5, establishment of cortical and medullar domains, and follicular development and maturation around the time of birth. The various cellular lineages that constitute the developing organs are listed on the left.

sperm. Ovaries, on the other hand, generate a characteristic cortical–medullary structure. Ovarian germ cells develop within the cortex to produce a defined number of oocytes (Zuckermann, 1951). During ovarian development, a single oocyte becomes enclosed by a somatic epithelial monolayer of flattened, squamous pregranulosa cells in a unit known as primordial follicle. Subsequent ovarian development will ultimately result in the production of mature follicles ready to be fertilized. A comprehensive review of mammalian gonadal development that also includes a comparative analysis of vertebrate species has been recently published elsewhere (DeFalco and Capel, 2009).

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B. Testis determination and differentiation As stated above, testis differentiation is induced by the expression of Sry in a subset of somatic progenitor cells (SPCs) (pre-Sertoli) that are destined to become Sertoli cells (Albrecht and Eicher, 2001; DeFalco and Capel, 2009; Sekido et al., 2004). Sertoli cells act as the organizing center of the testis where they are believed to direct the differentiation of all other gonadal cell types along the testis pathway. The differentiation from pre-Sertoli cells into Sertoli cells is characterized by the polarization of these cells, their aggregation around germ cells, and organization into distinctive testis cords (reviewed in Brennan and Capel, 2004; Wilhelm et al., 2007). Experiments in mice, combining embryos of XX and XY genotypes to generate chimeras, have demonstrated that the presence of Sertoli cells within the gonad at a minimum threshold of 20% is sufficient to promote testis development, indicating that even the XX supporting cell lineage lacking the cell-autonomous SRY can be induced to acquire the Sertoli cell fate (Burgoyne et al., 1995; Patek et al., 1991). Peritubular myoid cells (PMCs) form a single layer around Sertoli cells, circumscribing the testis cords. In vitro experiments show that PMCs support Sertoli cell differentiation and contribute to the deposition of the basal lamina thus defining the boundary between the testis cords and the interstitial tissue (Skinner et al., 1985; Tung et al., 1984). In the adult, PMCs promote the movement of mature sperm through the seminiferous tubules of the testis, a function mediated by their muscle-like character (Tripiciano et al., 1998). PMCs have no clear counterpart in the ovary. In addition to cells comprising testis cords, several other testis cell types reside in its other compartment, the interstitium (between the cords). These cells include endothelial cells, fibroblasts and different blood-derived cells, and most importantly Leydig cells. Leydig cells secrete hormones, including testosterone, that are required for establishing and maintaining secondary male characteristics (Bouin and Ancel, 1901). Fetal Leydig cells are first detected at E12.5, although their differentiation may begin earlier (reviewed in Maatouk and Capel, 2008). The developmental origin of the fetal Leydig cells has been controversial (e.g., Brennan et al., 2003; Jeays-Ward et al., 2003); the most recent evidence recognizes two distinct populations as contributing to Leydig cell formation: one arising from the coelomic epithelium (CE) and another from the gonad–mesonephric border (Defalco et al., 2011). In addition to secreting androgens, fetal Leydig cells are responsible for the production of insulin-like factor 3 that induces testis descent (Adham and Agoulnik, 2004; Feng et al., 2005; Nef and Parada, 1999; Zimmermann et al., 1999). They are also involved in stabilizing and reinforcing testis morphogenesis and are important for the normal development of Sertoli and germ cells (Tang et al., 2008). While both fetal and adult testis contain these steroidogenic cells, the adult Leydig cell population originates during puberty and is unlikely to be derived directly from the fetal cells (De Kretser and Kerr, 1994; for review, see Barsoum and Yao, 2010; Griswold and Behringer, 2009; and references therein).

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In parallel to Sertoli and Leydig cell differentiation, signals downstream of Sry induce cell proliferation resulting in a considerable increase in the embryonic testis size and the migration of cells from the neighboring mesonephros (Capel et al., 1999; Martineau et al., 1997; Schmahl et al., 2000). When mesonephric migration is artificially blocked, testis cords fail to form, indicating that the migrating cells are required for de novo cord formation (Martineau et al., 1997; Tilmann and Capel, 1999). It has been recently shown that the migrating cells give rise predominantly, if not exclusively, to endothelial cells that contribute to the formation of the male-specific vasculature characterized by the prominent arterial coelomic vessel (Combes et al., 2009a,b; Cool et al., 2008; Coveney et al., 2008). Evidence indicates that the formation of the testis vasculature is essential for normal testis cord structure pointing to the cooperation between the gonadal and the extragonadal cells in testis development (Cool et al., 2008, 2011).

C. Ovarian determination and differentiation In the mouse, the ovary is divided into two compartments: the outer portion of the ovary (the cortex) and the medulla, a highly vascular stroma in the center of the organ. The two main roles of the ovary are the production of steroid hormones and the generation of mature oocytes. The follicle is the functional unit of the ovary; it is comprised of a mature oocyte that is surrounded by the supporting granulosa cells (female counterpart of Sertoli cells) and the steroidogenic thecal cells (female counterpart of adult Leydig cells). In contrast to the testis, in which testis cords begin to form at E12.5, ovarian follicles do not differentiate until after birth. Similarly, unlike the comprehensive transformation outlined above that is taking place during embryonic testis differentiation, the female gonad does not undergo dramatic morphological changes until close to birth. While the ovary appears to remain dormant, female-specific gene expression is reported as early as E11.5 (Jorgensen and Gao, 2005; Menke et al., 2003; Nef et al., 2005; Yao et al., 2004). Most importantly, the oogonia within the ovary begin to enter meiosis at E12.5. Meticulous histologic analysis shows that the poorly differentiated XX gonad undergoes some remodeling between E13.5 and E15.5, where the PGCs develop as interconnected cysts linked by cytoplasmic bridges (Pepling and Spradling, 1998). The ovary also becomes highly vascularized by E13.5. In contrast to testis, the vasculature of the ovary presents itself as a dense network of small vessels only detectible using molecular markers (Bullejos et al., 2002). These vessels delineate strings of germ cells known as ovigerous cords (Konishi et al., 1986; Odor and Blandau, 1969). Ovarian germ cells accumulate in the cortex, while those lingering in the medulla eventually undergo programmed cell death (Yao et al., 2004). Germ cell development in mammals is described below in more details.

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D. Germ cell development In many species (including mammals), the PGCs do not arise within the genital ridge but journey there from the base of the allantois at the posterior end of the primitive streak. PGCs proliferate during all stages of migration to the genital ridges (Ginsburg et al., 1990; Tam and Snow, 1981). Once in the gonad, they continue to increase rapidly in numbers until they reach
25,000 cells by E13.5 (Donovan et al., 1986; Kemper et al., 1987; Tam and Snow, 1981). At this stage, they remain pluripotent and maintain the expression of the Oct4, Sox2, and Nanog (Chambers et al., 2007; Kehler et al., 2004; Pesce et al., 1998). The sex-specific development of germ cells depends on their environment; XX germ cells that integrate in a developing testis are incorporated in testis cords and adopt a male pattern of development. Similarly, XY germ cells developing in the female environment remain interspersed with somatic cells and follow the female developmental pathway by undergoing meiosis (Adams and McLaren, 2002; Burgoyne et al., 1992; Gubbay et al., 1990; Lovell-Badge and Robertson, 1990; McLaren and Southee, 1997). The control of cell cycle is essential for the development of germ cells in both XX and XY gonads and highlights the underlying antagonism between male and female developmental pathways. In the male, upon testis cord formation, the mitotically dividing PGCs arrest in the G0/G1 phase of mitosis and differentiate into T1-prospermatogonia, a state they remain in until after birth when they move to the periphery of testis cords and form a renewing population throughout adult male life (Hilscher et al., 1974). By contrast, in the XX gonad, germ cells enter meiosis between E12.5 and E13.5. These cells arrest in meiotic prophase as follicles begin forming around birth (Adams and McLaren, 2002; McLaren, 1984). Meiotic markers, such as gH2AX and SYN/COR, appear in the XX gonad in a rapid wave of expression from anterior to posterior beginning around E13.5 (Yao et al., 2003). Concomitantly, Oct4 expression is progressively downregulated, indicating loss of pluripotency (Menke et al., 2003). It has been previously proposed that entering meiosis could be an inherent property of germ cells; however, recent studies show that meiosis is tightly controlled. Specifically, it has been demonstrated that the signaling molecule retinoic acid (RA) is responsible for inducing meiosis in the ovary through the activation of the premeiotic marker stimulated by retinoic acid (Stra8) in the developing mouse gonocytes. In contrast, meiosis in the developing mouse testis is inhibited by the RA-degrading action of a P450 enzyme CYP26B1 (Anderson et al., 2008; Baltus et al., 2006; Bowles et al., 2006; Koubova et al., 2006; MacLean et al., 2007). Recent work has also highlighted the importance of Fgf9 and Nanos2 in actively promoting male cell fate in the germ cells in the testis (Barrios et al., 2010; Bowles et al., 2006; DiNapoli et al., 2006; Suzuki and Saga, 2008). Interestingly, testis cords can form in the genetically or pharmacologically induced absence of germ cells, demonstrating the negligible role of germ cells in this process (McLaren, 1991; Merchant, 1975). However, meiotic germ cells in XY

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gonads are capable of interfering with testis development by antagonizing mesonephric migration and cord formation (Yao et al., 2003). Similarly, during the fetal stages of ovarian development, neither does germ cell loss appear to have detrimental effects on the somatic pathways responsible for ovarian differentiation (Guigon and Magre, 2006), nor does it seem to affect the formation of the cortical/medullary domains toward the end of fetal life (Merchant-Larios and Centeno, 1981). Germ cells are nonetheless required for the morphological development of the ovary after birth (Merchant-Larios and Centeno, 1981). In their absence, follicles degenerate into cord-like structures and XX cells express male markers such as Sox9 and Mis (Mu¨llerian inhibitory substance) (Couse et al., 1999).

II. MOLECULAR CONTROL OF GONADAL DEVELOPMENT In the mouse, gonads begin to form around day 10 of embryonic development (E10.0). At this stage, all somatic cells of XX and XY gonads are positive for steroidogenic factor 1 (Sf1), Lim-like homeodomain protein 9 (Lhx9), the pairedlike homeobox gene (Emx2), and the Wilms tumor gene (Wt1). Correspondingly, ablation of any of these genes results in the regression of the gonad in both sexes by E11.5 (Birk et al., 2000; Kreidberg et al., 1993; Luo et al., 1994; Miyamoto et al., 1997). Expression patterns in the XX and XY gonads are comparable prior to E11.5: Fgf9, a male-promoting factor, is expressed in the coelomic domain of the gonad, while the female-inducing signal Wnt4 is restricted to a domain comprising the gonad/mesonephros border (Kim et al., 2006b). In addition, Sox9 (Sry-like HMG-box protein 9) is also expressed at very low levels in both XX and XY gonads (Morais da Silva et al., 1996). At this stage (called bipotential or indifferent), the gonad is suspended ready to embark on either developmental path. In the male, the role of SRY is to trigger the differentiation of the supporting somatic precursor cell into Sertoli cell (and not follicle cell) (Albrecht and Eicher, 2001; Palmer and Burgoyne, 1991; Sekido et al., 2004). This fate decision depends on whether or not low-level Sox9 expression is further induced or repressed. If a high level of Sox9 expression is established, the supporting cell will develop into a Sertoli cell in the testis. Conversely, in the ovary where Sox9 is repressed, the supporting cell develops as a follicle. This notion is supported by gain-of-function experiments where upregulation of Sox9 in XX transgenic gonads results in the initiation of testis development (Qin et al., 2004; Vidal et al., 2001).In contrast, deletion of Sox9 in mice results in a male-to-female sex reversal (Barrionuevo et al., 2009; Chaboissier et al., 2004). Recent evidence confirmed the long-held belief that SRY acts by boosting the expression of Sox9 through binding to SRY-response elements in the Sox9 regulatory region and activating its expression (Sekido and Lovell-Badge, 2008). SOX9 is also known to trigger its own expression in an autoregulatory loop (Sekido and LovellBadge, 2008). The timing and levels of Sry expression are critical for the proper initiation of the testis-determining pathway. Mutations causing reduced or delayed

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expression of Sry result in partial or complete sex reversal (Albrecht and Eicher, 1997; Capel et al., 1993; Nagamine et al., 1998). In addition to the principal role of SRY, two antagonistic signals influence the establishment of male pattern of Sox9 expression. FGF9 has been shown to promote Sox9 expression, while WNT4 has a repressing effect on Sox9 (Kim et al., 2006b). Upon its activation, Sox9 is believed to work together with Fgf9 in a feed-forward loop that ultimately results in the silencing of Wnt4. Thus, Sox9 expression is necessary and sufficient to activate the testis gene expression program and the subsequent steps in testis development. In the female gonad where SRY is absent, Sox9 expression is not enhanced, Fgf9 is silenced, and Wnt4 expression becomes elevated. Ovarian WNT4 acts to further downregulate both Fgf9 and Sox9, as Wnt4-null XX gonads transiently express these genes in the absence of Sry (Kim et al., 2006b). Until recently, the somatic cells in the fetal ovary have received little attention mostly because ovarian differentiation lacks dramatic elements comparable to their male counterparts. Given that meiosis was deemed to be a cell-autonomous process in germ cells, it was not immediately clear what other demands would impel the embryonic ovary to engage in a tissue-specific gene expression program. Original experiments by Jost et al. (1953) that demonstrated female development to be independent of gonadal hormones, coupled with the discovery of genetically dominant roles for the testis determining pathway and its regulators Sry and Sox9, led to the prevailing view that ovarian development is the “default” state. However, as Eicher and others have emphasized, ovarian specification and development must also be controlled by an active genetic pathway (Eicher and Washburn, 1986). The search for an “ovary-determining” factor led to the identification of several genes that initially appeared to meet the requirements. Dax1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene1) was one of the first prospective ovary-determining factors based on its function as a transcriptional regulator, its X-linked nature (Swain et al., 1998), and evidence that a duplication of this gene in humans leads to female development in XY patients (Bardoni et al., 1994). However, Dax1-null female mouse embryos exhibited normal ovarian development (Meeks et al., 2003a,b; Yu et al., 1998). Instead of being an ovary-determining gene, Dax1 is described as having antitestis properties, as a duplication of a Dax1-containing piece of the X chromosome in XY humans, and transgenic mice harboring multiple copies of the gene both result in the male-to-female sex reversal (Swain et al., 1998; Zanaria et al., 1994). The forkhead transcription factor Foxl2 has also been considered as a female-determining factor because of its potential association with female-tomale sex reversal in the PIS (polled intersex syndrome) goats (Pailhoux et al., 2001). Human patients carrying mutations in the FOXL2 gene display BPES (blepharophimosis/ptosis/epicanthus inversus syndrome), an autosomal disease characterized by eyelid defects and premature ovarian failure (Crisponi et al., 2001; Pailhoux et al., 2001). In mice, Foxl2 initiates expression in the XX gonad

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as early as E11.5 and marks the commitment of the supporting cell lineage to the follicle cell fate (Wilhelm et al., 2009). Despite the fact that Foxl2 deficiency results in ovarian failure in the adult (Schmidt et al., 2004), the initial development of the ovary in these mice is unaffected (Ottolenghi et al., 2005; Schmidt et al., 2004), making it unlikely to be the female-determining factor. In the adult ovary, Foxl2 is essential for the maintenance of somatic cell identity. Inducible deletion of Foxl2 in adult ovarian follicles leads to upregulation of Sox9, transdifferentiation of granulosa cells into Sertoli cells, and appearance of testis structure and cell types (Uhlenhaut et al., 2009). In recent years, the notion of having one single ovarian-determining gene gave way to a less conservative hypothesis where more than one player is required for the initial development of the ovary. While Dax1 and Foxl2 did not hold up to be critical for the establishment of the somatic cell program in the developing ovary, two genes, Wnt4 and Rspo1, appeared to fit the criteria. At the bipotential stage, Wnt4 and Rspo1 are expressed in both male and female gonads. This expression becomes female specific by E12.5. Female embryos lacking functional Wnt4 develop several ovarian defects including the formation of ectopic testis vasculature, the emergence of androgen-producing cells, the appearance of male-specific structures at birth, and the loss of female germ cells beginning at E15.5 (Biason-Lauber et al., 2004; Jeays-Ward et al., 2003; Vainio et al., 1999; Yao et al., 2004). Prior to E15.5, germ cells in XX Wnt4 mutant gonads were able to enter meiosis (Yao et al., 2004), indicating that the deletion of Wnt4 does not impair or reverse this ovarian function and therefore Wnt4 does not act alone in determining the ovarian fate. Studies in sex-reversed human XX patients first implicated Rspo1 as a potential ovarian-determining gene. These patients developed testes in a female genetic background and were harboring disrupting mutations in the RSPO1 gene (Parma et al., 2006). Mice lacking functional Rspo1 develop ovarian defects similar to Wnt4 mutants, where ovarian development is impaired but without a complete sex reversal (Chassot et al., 2008; Tomizuka et al., 2008). In addition to the shared defects between Rspo1 and Wnt4 mutant animals, evidence that these two genes may cooperate to promote the ovarian pathway came from a study of a human XY patient with male-to-female sex reversal. This patient was shown to carry a duplication of the portion of chromosome 1 that contains both WNT4 and RSPO1 loci (Elejalde et al., 1984; Jordan et al., 2001). More recent evidence stemming from the analysis of mice with deficiencies in both Foxl2 and Wnt4 supports the notion that the two factors act in a cooperative manner to maintain female sexual identity. While loss of Foxl2 alone is not sufficient to block female development, deletion of both Foxl2 and Wnt4 in XX mice leads to testis differentiation, including the formation of testis cords and differentiation of germ cells into spermatogonia (Ottolenghi et al., 2007). Ottolenghi et al. also showed that ectopic expression of Foxl2 in XY transgenic mice impairs testis tubule differentiation. These results are all consistent with an antitestis role for Foxl2.

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III. CANONICAL WNT SIGNALING CONTROL OF GONADAL DEVELOPMENT In vertebrates, the Wnt family comprises 19 secreted proteins that play decisive roles during development, including embryonic induction, generation of cell polarity, and cell differentiation. Wnts are generally believed to activate three different pathways upon binding to different Wnt receptors: the canonical Wnt/b-catenin cascade, the noncanonical planar cell polarity pathway, and the Wnt/Ca2þ pathway (reviewed in Huang and He, 2008; Katoh, 2005; Kohn and Moon, 2005). The canonical Wnt signaling pathway is the best understood; it is triggered by the binding of a WNT ligand to the Frizzled (Fz) and Low Density Lipoprotein (LDL)-related receptor protein (LRP) 5/6 coreceptors ultimately leading to the stabilization and nuclear translocation of b-catenin protein. In the absence of WNT ligand, cytoplasmic b-catenin is recruited by a group of proteins known as the “destruction complex” composed of Axin, the tumor suppressor APC, glycogen synthase kinase 3b, and casein kinase I (Kimelman and Xu, 2006). In this “off-state,” b-catenin is phosphorylated by the kinases and targeted for degradation via ubiquitin-mediated proteasomal pathways. However, upon activation of the Wnt receptor complex, the disheveled (Dsh) protein is recruited to the Fz receptor, this, in turn, results in the inhibition of the intrinsic kinase activity of the APC complex for b-catenin. The exact sequence of events here is still unclear, but it likely involves the Wnt-induced recruitment of Axin to the phosphorylated tail of LRP and/or to Fz-bound Dsh (Aberle et al., 1997; Kishida et al., 1998; Liu et al., 2002; Xing et al., 2003). As a result, b-catenin accumulates in the cytoplasm and translocates into the nucleus where it binds to TCF/LEF transcription factors, along with other associated proteins. b-Catenin/ TCF/LEF transcription complex recognizes TCF/LEF consensus binding sites in DNA and activates transcription of Wnt target genes (Behrens et al., 1996; Molenaar et al., 1996; van de Wetering et al., 1997). Several regulatory molecules have been reported to interact with WNT proteins and their receptors and modulate the activity of the canonical Wnt/b-catenin signaling pathway (reviewed in Kikuchi et al., 2007). DKK1, a member of the Dickkopf family of secreted proteins, acts as an antagonist of canonical Wnt signaling. The mechanism of Dkk1 inhibition of the canonical Wnt pathway has been suggested to depend upon its high-affinity binding to the LRP5 or LRP6 coreceptors disrupting the formation of the Fz-LRP5/6 receptor complex (Bafico et al., 2001; Mao et al., 2001; Semenov et al., 2001). DKK1 can also block Wnt signaling by binding to LRP6 and the Kremen receptors thus inducing the internalization of LRP6 (Mao et al., 2002). R-spondins (RSPOs) represent another family of soluble proteins that have been established as regulators of the canonical Wnt signaling pathway (Kim et al., 2006a,b). The biochemical mode of action of RSPO proteins is not

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well understood. It is thought that they activate Wnt/b-catenin signaling by either directly interacting with WNT proteins or facilitating the formation of the Fz/LRP receptor complex (Kazanskaya et al., 2004; Nam et al., 2006). It was also suggested that RSPOs could act through an alternative WNT-independent pathway to induce b-catenin activation (Kim et al., 2005, 2006a,b). Yet, another group proposed that Rspo1 could be regulating Wnt signaling by preventing DKK1/ Kremen-mediated internalization of the LRP5/6 coreceptor (Binnerts et al., 2007). Biochemical evidence presented above suggests that both RSPO1 and WNT4 may exert their action through the canonical Wnt signaling intracellular regulator b-catenin (Kim et al., 2006a,b; Mizusaki et al., 2003; Park et al., 2007). Given the roles of WNT4 and RSPO1 in the establishment of the somatic cell environment in the fetal ovary, several investigators focused their attention on bcatenin as a potential regulator of the female pathway. Compelling evidence that further strengthened the connection between the canonical Wnt pathway and ovarian differentiation came from loss-of-function studies where b-catenin was specifically inactivated in the SF1-positive ovarian somatic cells. These Sf1Cre, bcatflox/flox mutants exhibited ovarian defects similar to those found in Wnt4 and Rspo1 knockouts (Liu et al., 2009; Manuylov et al., 2008). The involvement of b-catenin was also confirmed by gain-of-function experiments where ectopic activation of this regulator in SF1-positive cells resulted in partial sex reversal (Maatouk et al., 2008). Additionally, ectopic expression of this regulatory molecule in the absence of Rspo1 and Wnt4 restores normal ovarian development (Chassot et al., 2008; Liu et al., 2010). While Wnt4 expression is lost in ovaries lacking b-catenin, Rspo1 expression remains unchanged, indicating the requirement of both RSPO1 and b-catenin for Wnt4 activation (Liu et al., 2009; Manuylov et al., 2008). RSPO1 and WNT4 are able to activate b-catenin in vitro (Binnerts et al., 2007; Kim et al., 2008; Wei et al., 2007). It is still unclear, however, whether WNT4 and RSPO1 act in a linear fashion or synergistically to activate b-catenin in the somatic cells of the ovary. In addition to the genes discussed above, a number of other candidates most of which were revealed by various high-throughput techniques (e.g., microarrays) to have enriched expression in ovaries compared to testes are still awaiting their functional evaluation in ovarian development (Bouma et al., 2007a; Menke and Page, 2002; Nef et al., 2005). The GATA4–FOG2 transcriptional complex is also implicated in sex determination and gonadal differentiation. Its involvement is discussed in detail in the following section.

IV. THE GATA–FOG TRANSCRIPTIONAL PARTNERSHIP GATA proteins are a class of lineage-restricted zinc finger transcription factors that play key roles in controlling proliferation, cell fate outcome, and cell maturation (reviewed in Molkentin, 2000; Morceau et al., 2004; Patient and

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McGhee, 2002). GATA proteins derive their name from the DNA consensus sequence, (T/A)GATA(A/G), to which they bind with high affinity and specificity (Lowry and Atchley, 2000). The GATA protein family in vertebrates consists of six members: GATA1/2/3 that are enriched in the hematopoietic lineages and GATA4/5/6 that are expressed in various mesoderm and endoderm-derived tissues such as heart, gonads, and gastrointestinal tract (Arceci et al., 1993; Cantor and Orkin, 2002; Grogan and Locksley, 2002; Laverriere et al., 1994; Morrisey et al., 1996, 1997a,b; Ohneda and Yamamoto, 2002). A signature motif defining vertebrate GATA proteins comprises two highly conserved zinc finger domains designated as N-terminal and C-terminal fingers. DNA-binding activity occurs mostly through the C-terminal zinc finger and adjacent basic regions, while N-terminal finger plays an auxiliary role (Yang and Evans, 1992). GATA proteins are thought to contain at least one transactivation domain (Martin and Orkin, 1990); for example, GATA4 contains two such domains within the N-terminus of the protein and a minor transactivation domain in the C-terminal region (Molkentin, 2000; Morrisey et al., 1997a,b; Tremblay et al., 2002). In addition to employing their zinc finger domains for DNA binding, GATA proteins can use either N- or C-terminal zinc finger to associate with different cofactors. The FOG (friend of GATA) cofactors modulate the activity of GATAs by interacting with the N-terminal finger, while other cofactors such as p300/CBP do so through the C-terminal finger (Blobel et al., 1998; Dai and Markham, 2001; Tevosian et al., 1999; Tsang et al., 1997; see Cantor and Orkin, 2005 for review). FOG proteins are multitype zinc finger proteins that have been shown to act as transcriptional coactivators or corepressors of GATA factors depending on the cellular context and target genes (Fossett et al., 2001; Gaines et al., 2000; Tsang et al., 1997). There are two FOG proteins in mammals: FOG1 and FOG2. FOG1 (ZFPM1 - Mouse Genome Informatics) that was the first to be characterized as a GATA1 cofactor (Tsang et al., 1997) has been implicated in hematopoietic development. Fog1/ mice die between E10.5 and E12.5 of severe anemia. They exhibit a block in erythroid maturation, as well as a complete failure in megakaryopoeisis (Chang et al., 2002; Tsang et al., 1998) and defects in T lymphocyte development (Zhou et al., 2001). In addition to its role in hematopoiesis, FOG1 is important for cardiac development (Katz et al., 2003). FOG2 (ZFPM2 - Mouse Genome Informatics), the second member of the FOG family, is expressed outside of blood, mostly in the heart, brain, gonads, and liver (Lu et al., 1999; Svensson et al., 1999; Tevosian et al., 1999). While both FOG proteins are indispensable and play nonoverlapping roles during cardiac development (Katz et al., 2003; Tevosian et al., 2000), only FOG2 plays critical roles in gonadal development (Tevosian et al., 2002). In vitro FOG2 overexpression studies demonstrate the ability of this cofactor to repress the GATA4dependent transcription of several cardiac- and gonadal-specific gene promoters

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(Robert et al., 2002; Svensson et al., 1999); however, the exact mechanisms by which FOG modulates GATA transcriptional activity are not known. While FOGs possess zinc finger motifs that are capable of binding DNA, to date there is no evidence that FOG proteins or their fly homologue U-shaped (USH) bind to specific sites in DNA (Cubadda et al., 1997; Haenlin et al., 1997; Tevosian, Sergei and Orkin, Stuart, unpublished observations). Consequently, FOGs are thought to modulate GATA transcriptional activity through the recruitment of other proteins, such as chromatin remodeling proteins, to DNA sites occupied by GATA proteins. Studies show that both FOG1 and FOG2 associate with the nucleosome remodeling and histone deacetylase repressor complex to mediate the transcriptional repression by GATA proteins (Hong et al., 2005; Roche et al., 2008). The biochemical principles underlying GATA and FOG proteins’ function have emerged largely from studies of hematopoietic development that benefit from the readily available robust and reliable cell culture approaches. These advances have been recently reviewed elsewhere (Bresnick et al., 2010; Kaneko et al., 2010). While these studies have provided invaluable insight for understanding the function of GATA–FOG complexes in hematopoiesis, it remains to be confirmed whether molecular model that involves GATA “switching” is universally applicable.

V. GATA4–FOG2 CONTROL OF GONADAL DEVELOPMENT A. Gonadal expression of GATA and FOG proteins Three GATA members, Gata2, Gata4, and Gata6, have been detected in fetal mouse gonads. Gata1 only appears in the Sertoli cells of the postnatal testis, which are, intriguingly, the only known extrahematopoietic site of Gata1 expression. Gata2 is expressed in the ovarian germ cells and in the mesonephros of both XX and XY gonads but is absent from the gonadal somatic cells (Siggers et al., 2002). Several reports documented the expression of Gata6 in the developing mammalian testis and ovary, in both the somatic and the germ cells (Heikinheimo et al., 1997; Ketola et al., 1999; Laitinen et al., 2000; Lavoie et al., 2004; Robert et al., 2002). The timing of initiation for Gata6 gonadal expression has not been precisely pinpointed due to its relative weakness compared to that of Gata4, but it could be as early as E13.5 (Robert et al., 2002). GATA1 is not expressed by Sertoli cells until the first wave of spermatogenesis. In the adult animals, GATA1 expression in Sertoli cells coincides with VII–XI stages of spermatogenesis and appears to be dependent on the presence of maturing germ cells (Ito et al., 1993; Yomogida et al., 1994). Conditional knockout of Gata1 in Sertoli cells using Dhh promoter-based Cre recombinase did not yield a notable phenotype, most likely due to redundancy with Gata4

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(Lindeboom et al., 2003). Additional evidence that Gata1 is dispensable for testis function was provided by the analysis of hematologically rescued GATA1 mice. These Gata1-null (Gata1/Y) animals carry a GATA1-expressing transgene that is active in blood but not testis. Despite the absence of GATA1 expression, the morphology of the testes was normal and the males were fertile (Fujiwara et al., 2004). Gata4 is currently the only member of the GATA family that has been unequivocally shown to appear in the somatic cell lineages of the developing gonadal anlagen (Heikinheimo et al., 1997; Viger et al., 1998). GATA4 expression is present prior to the onset of sex determination in the gonadal primordia (e.g., Albrecht and Eicher, 2001; Defalco et al., 2011), and it is retained at E11.5 in the somatic cells of both XX and XY gonads. At E13.5, Gata4 expression becomes enhanced in the Sertoli cell lineage in XY gonads, while expression in the interstitial cells of XY gonads as well as in all cells of XX gonads slightly decreases (but still remains easily detectable). Gata4 expression is maintained through adulthood in the testis and is augmented in the granulosa cells of adult ovaries (Heikinheimo et al., 1997; Viger et al., 1998). The expression of a FOG family member, Fog2, has been reported in the developing mouse gonad as early as E11.5 (Lu et al., 1999; Svensson et al., 1999; Tevosian et al., 1999). Fog2 is also expressed in cardiac and nervous tissues and is required for mouse cardiac development (Tevosian et al., 2000).

B. The role of GATA and FOG proteins in sex determination and early gonadal development It has been postulated that GATA4 is important for Mu¨llerian duct regression through its activation of Amh (anti-Mu¨llerian hormone)/Mis gene. Evidence of this regulation is derived from in vitro studies showing that GATA4 binds to its consensus sites in the Mis promoter resulting in the activation of a reporter cassette expression (Viger et al., 1998; Watanabe et al., 2000). Gata4-null mutants have been generated (Kuo et al., 1997; Molkentin et al., 1997); however, these Gata4/ embryos die at approximately E8.0 when they develop cardia bifida. Such an early demise of Gata4 null embryos precluded analysis of GATA4’s role in gonadogenesis in these animals. The first in vivo evidence of the importance of GATA4 and its cofactor FOG2 in gonadogenesis was provided through the analysis of Gata4ki/ki and Fog2/ mutant mice (Crispino et al., 2001; Tevosian et al., 2000, 2002). Fog2/ embryos survive until
E14.5 (Svensson et al., 2000; Tevosian et al., 2000), making possible the analysis of early gonad development in the absence of FOG2. To evaluate the role for GATA4 in the context of gonadogenesis, Tevosian et al. (2002) took advantage of the recently developed Gata4 knock-in allele (Gata4ki, a V217G amino acid substitution) that abrogates

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the interaction between GATA4 and FOG2 (or FOG1) (Crispino et al., 2001). Homozygous Gata4ki embryos survive to E13.5 when they then die from cardiac abnormalities similar to those noted in Fog2/ embryos (Crispino et al., 2001). This Gata4ki allele allows unique insight into the importance of GATA4–FOG interaction in mammalian gonad development. Both Gata4ki/ki and Fog2-null mutants exhibit similar defects in gonadal differentiation (Manuylov et al., 2008; Tevosian et al., 2002). Specifically, testicular cords in XY gonads failed to form by E13.5, and Wt1 and Sf1 gene expression remained similar to that in XX gonads. While Sry gene expression was initiated in both Gata4ki and Fog2 mutant XY gonads (but at significantly lower levels than the wild-type counterpart), the expression of several genes downstream of SRY that are crucial for normal Sertoli cell function, namely Sox9, Mis, and Dhh (Behringer et al., 1994; Bitgood et al., 1996; Kent et al., 1996; Morais da Silva et al., 1996) was completely absent. In addition, transcripts encoding steroidogenic enzymes P450scc (Cyp11a1), 3bHSD (Hsd3b3), and P450c17 (Cyp17a1) were also lost. These genes mark the emerging Leydig cell lineage, and their products are essential for the onset of testosterone synthesis (Greco and Payne, 1994). Taken together, these findings demonstrate that in the male, GATA4 and its ability to interact with FOG2 are essential for the determination and differentiation of the testis (Fig. 4.2). While this work established the requirement for the GATA4–FOG2 complex in testis differentiation, it remained unclear whether its function was restricted to the (direct or indirect) regulation of Sry gene. Indeed, it could be argued that a decrease in Sry expression in Fog2-null mutants was solely responsible for the subsequent block in male development. This ambiguity was clarified by taking advantage of dominant sex reversal mouse models. XX mice with the Ods transgenic insertion (Bishop et al., 1999) or the Wt1-Sox9 YAC transgene (Vidal et al., 2001) overexpress the testis differentiation gene, Sox9. As a result of this ectopic expression, XX animals undergo dominant sex reversal by developing into phenotypically normal, but sterile, males. It was determined that Fog2 haploinsufficiency prevents (suppresses) the dominant sex reversal and Fog2þ/; Wt1Sox9 or Fog2þ/; Ods XX animals develop normally—as fertile females (Manuylov et al., 2007). These findings were important because they provided evidence that the sex reversal observed in the transgenic XX gonads relies on GATA4–FOG2dependent gene targets other than the Y chromosome-linked Sry gene. Fog2 haploinsufficiency leads to a lower number of SOX9-positive cells in XY gonads (Bouma et al., 2007b; Manuylov et al., 2007). Similarly, the 50% reduction of Fog2 levels in Fog2þ/; Wt1-Sox9 females is associated with an
50% downregulation of Sox9 expression, an effect possibly accounting for the suppression of sex reversal in these mutants. Intriguingly, Fog2-null or Gata4ki/ki embryos (either XX or XY) fail to express detectable levels of Sox9 despite carrying the Ods mutation or Wt1-Sox9 transgene. This result is not immediately

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Figure 4.2. Control of mammalian sex determination by GATA4-FOG2 partnership. The GATA4–FOG2 partnership contributes to the activation of Sry expression in the male. SRY (most likely assisted by GATA4–FOG2 complex) in turn upregulates Sox9 expression. Once SOX9 levels reach a critical threshold, a positive regulatory loop is initiated between SOX9 and FGF9. Activation of SOX9 further promotes the testis pathway through the upregulation of several male-specific genes including Amh/ Mis. GATA4 is also believed to act in activating male gene (e.g., Amh/Mis) expression early in testis differentiation. In the female, GATA4–FOG2 complex contributes to the upregulation of Wnt4 expressionnot only through the repression of Dkk1 but also through alternative pathways. WNT4 together with RSPO1 activates the canonical Wnt signaling pathway resulting in the accumulation of b-catenin. b-Catenin activates target genes such as Fst and Foxl2 and also upregulates Wnt4 expression. High WNT4 levels in turn repress Fgf9 and Sox9 leading to the establishment of the female pathway. FST antagonizes the action of activin B, the protein product of inhbb gene, and formation of testis-specific vasculature in the XX gonad. At later stages, FOXL2 maintains granulosa (follicle) cell identity by repressing Sox9 expression. In the testis, SOX9 probably represses ovarian genes, including Wnt4 and Foxl2. Solid lines, validated regulation; dashed line, plausible regulation.

explicable with respect to the Wt1-driven Sox9 transgene, as Wt1 gene expression in gonadal somatic cells does not require GATA4–FOG2 complex (Manuylov et al., 2007). The identification of a number of sexually dimorphic genes expressed in the mouse ovary (Bouma et al., 2007a; Chassot et al., 2008; Jorgensen and Gao, 2005; Menke and Page, 2002; Nef et al., 2005; Vainio et al., 1999; Yao et al., 2004) paved the way for clarifying roles for GATA4 and FOG2 in ovarian development

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(Manuylov et al., 2008). The GATA4–FOG2 complex was shown to be required for the expression of Wnt4 as well as its downstream target Fst. Importantly, these studies also showed that in the absence of GATA4–FOG2 interaction, DKK1 (a secreted inhibitor of the Wnt pathway) is ectopically activated in the ovary, and that this activation is coupled with loss of expression for several genes linked to the canonical Wnt signaling. These results strongly suggest that the GATA4–FOG2 complex controls female sexual development at least in part through the repression of Dkk1, which, in turn, allows the unabated function of the canonical Wnt signaling pathway (Manuylov et al., 2008). In addition, loss of GATA4–FOG2 interaction results in the dramatic downregulation of the forkhead transcription factor Foxl2. Foxl2 is one of the earliest expressed female-specific genes, and it is essential for female reproductive development (see above; reviewed in Uhlenhaut and Treier, 2006). Interestingly, while Foxl2 expression is also downregulated in ovaries lacking b-catenin, it remains unperturbed in Wnt4-null and Rspo1-null ovaries (Chassot et al., 2008; Manuylov et al., 2008), suggesting that GATA4–FOG2 and b-catenin regulate Foxl2 expression independently of WNT4 and RSPO1. While GATA4–FOG2 transcriptional regulation appears to be pivotal for the normal expression of most ovary-specific genes, some dimorphically expressed genes escape this regulation. The normal expression in the absence of GATA4–FOG2 interaction is particularly surprising in the case of Bmp2, as it is not expressed in Wnt4-null XX gonads. Rspo1, another gene that plays an essential role in ovarian development (Chassot et al., 2008), also remains unperturbed in Gata4–Fog2 mutants (Manuylov et al., 2008). These results clearly demonstrate that the GATA4–FOG2 complex is essential for the selective control of gene expression and somatic cell differentiation in the ovary (Fig. 4.1). Because Gata4 and Fog2 mutants survive until E13.5, Manuylov et al. were able to also confirm the initiation of germ cell differentiation in these mutants (Manuylov et al., 2008). Their observations indicate that loss of GATA4–FOG2 does not affect germ cell meiotic progression, as these cells appropriately express meiotic markers at the same time as controls, beginning at E12.5. Taken together, these findings established GATA4, FOG2, and their interaction as essential regulators of sexual differentiation both in males and females.

C. Differential regulation of target genes by GATA4–FOG2 complex and canonical WNT signaling in the ovary The connection between the GATA4–FOG2 transcriptional regulation and the WNT signaling pathway during ovarian development has previously been established (Manuylov et al., 2008). Based on epistatic analyses, GATA4–FOG2 appeared to act upstream of the WNT pathway; however, parallel regulation was also possible. Taking advantage of the Fog2 knockout (Svensson et al., 2000;

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Tevosian et al., 2000) and the Catnblox(ex3) (b-catfl.ex3) transgenic mouse line in which b-catenin is stabilized by the Cre-mediated excision of exon3 that is responsible for its degradation (Harada et al., 1999), three distinct groups of GATA4–FOG2- and WNT-regulated genes in the ovary have been defined. Genes that are under strict GATA4–FOG2 control, or strict WNT signaling regulation, and those that may require both pathways for their activation were identified (Fig. 4.3; Zaytouni et al., in preparation). Available evidence distinguishes one female-specific gene, Sprr2d (small proline-rich 2d) (Beverdam and Koopman, 2006), that belongs to the first group. Sprr2d expression is downregulated in Gata4ki/ki and Fog2/ ovaries but not in ovaries lacking functional b-catenin (Manuylov et al., 2008). Additionally, Sprr2d expression is not upregulated in XY gonads with stabilized b-catenin (Zaytouni et al., in preparation), suggesting that this gene is not regulated by the canonical WNT signaling pathway. In contrast, Lee et al. (2009) show that Sprr2d expression levels were reduced in Wnt4/ to 61% of the control suggesting that Wnt4 can partially regulate Sprr2d through a noncanonical pathway. The homeobox transcription factor Msx1 was recently identified in a microarray analysis as a target of GATA4–FOG2 regulation in the ovary. A closer examination of Msx1 regulation, however, suggests that it belongs to the group of genes that are under strict WNT signaling regulation. While Msx1 expression is lost in Gata4ki/ki and Fog2/ ovaries, it is also downregulated in ovaries lacking

GATA4-FOG2

Dkk1 b-Catenin

Rspo1

Wnt4

Sox9 Fgf9 Sp5 Msx1

Fst Foxl2

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Figure 4.3. A genetic model of target gene regulation by the GATA4–FOG2 complex and the canonical WNT signaling in the ovary. GATA4–FOG2 complex regulates Sp5 and Msx1 genes indirectly through the Wnt/b-catenin pathway. Fst, Foxl2, and Dkk1 belong to a group of genes that require input from both pathways for their regulation. b-Catenin can act as a repressor of Dkk1 in the absence of GATA4–FOG2 interaction. Sprr2d is so far the only known example of a gene that is regulated in the ovary by the GATA4–FOG2 complex independently of the canonical WNT signaling pathway.

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functional b-catenin. Conversely, ectopic activation of b-catenin in XY gonads results in the upregulation of Msx1. Zaytouni et al. also showed that Msx1 regulation by GATA4/FOG2 is indirect, as the requirement for this complex can be bypassed by the ectopic activation of canonical WNT signaling in Fog2/ gonads. In addition to Msx1, another gene belonging to this group is the female-specific gene Sp5, which encodes a member of the Sp1 family of transcription factors (Harrison et al., 2000). Sp5 expression is downregulated in Fog2/ gonads Wnt4/ as well as ovaries lacking functional b-catenin (Manuylov et al., 2008). Consistent with these observations, Sp5 expression is activated in XY gonads upon ectopic WNT signaling activation. Additionally, Sp5 expression is rescued in Fog2/ mutant gonads where canonical WNT signaling is restored suggesting that it is indeed a direct target of canonical WNT signaling regulation, and that this regulation does not require the GATA4–FOG2 transcriptional complex (Zaytouni et al., in preparation). Of the genes tested, the majority belonged to the last group; Dkk1, a WNT signaling inhibitor previously shown to be a target of GATA4–FOG2 (but not WNT/b-catenin) inhibition (Manuylov et al., 2008), was also inhibited by b-catenin in a Fog2-deficient background, suggesting that if GATA4–FOG2 is not available to repress DKK1, the canonical WNT pathway can assume that role. Similar to Dkk1, the female-specific genes, Fst and Foxl2, require the input of both GATA4–FOG2 and canonical WNT signaling for their regulation as their expression was upregulated in XY gonads upon b-catenin stabilization but failed to be rescued in Fog2-null gonads where canonical Wnt signaling is restored.

D. Conditional targeting reveals additional roles for GATA4/FOG2 proteins in gonadal development Analysis of embryos carrying Gata4ki or Fog2-null mutation firmly established that the GATA4–FOG2 complex controls the early steps in the commitment of SPCs to their respective sex fates. However, embryonic lethality at mid-gestation precluded the evaluation of GATA4/FOG2 function in gonadal development and gene regulation at later stages. The observation that the Gata4ki mutation and Fog2 knockout similarly affected the development of either testis or ovary was consistent with the notion that, during sex determination and early gonadal development, both proteins act as a complex. This observation was somewhat at odds with biochemical work that identified a repression domain in FOG2 (Robert et al., 2002; Svensson et al., 1999) and demonstrated that FOG2, at least in some settings, reverses the transactivation by GATA4. This predicts that loss of GATA4 (an activator) may have a different or even opposite effect compared to the loss of FOG2 (a repressor). Similar, analysis of GATA–FOG interaction in hematopoiesis provided evidence that FOG (in this case FOG1) is found associated with GATA1 only at some, but not other, promoters (e.g., Letting et al., 2004). Hence, it is possible that, in later stages of sexual

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differentiation, the roles for GATA4 versus GATA4–FOG2 complex could diverge. Finally, while analysis of animals with the Gata4ki mutation firmly tied GATA4 to gonadal development as a part of the GATA4–FOG2 complex, these studies could not address the specific role of the GATA4 protein. An important insight into these questions was provided by the analysis of mice with conditional deletions of Gata4/Fog2 genes (Manuylov et al., 2011). Both genes have been specifically deleted in the somatic cells of the gonad using Sf1Cre. Additionally, Gata4 was ablated with tamoxifen-inducible Wt1CREERT2 to accomplish time-dependent gene deletions. Sf1Cre-mediated excision led to a profound loss of Gata4 expression at E12.5. Given that previous data demonstrated a comprehensive differentiation block upon the loss of GATA4–FOG2 interaction (Tevosian et al., 2002), one could have predicted that expression of most testis-associated genes will be lost or, at least, diminished. This, however, turned out not to be the case; Sf1Cre/þ; GATA4fl/ fl (hereafter referred to as GATA4SF) mice did not succumb to the early arrest of gonadal development observed in the fetuses with GATA4ki genotype. This discrepancy is most easily reconciled considering that timing of Gata4 gene loss in conditionally targeted animals now follows (and not precedes) sex determination. Many GATA4-positive cells are still observed in the GATA4SF gonad at E11.5, during the critical time of commitment to sex determination, with the excision mostly complete only at E12.5. Not surprisingly, sex determination and testis differentiation in the GATA4SF mutants initiated quite normally. In contrast, contemporaneous E11.5 Gata4ki mutant gonads are already undergoing major changes (e.g., abnormal expression of Dkk1; Manuylov et al., 2008) resulting in the inability of Gata4ki or Fog2-null somatic progenitors (Sf1þ; Wt1þ) to commit to the Sertoli or granulosa fates. This developmental block is corroborated by the absence (or at least dramatic downregulation) in the expression of either male(Sox9, Amh/Mis, Dhh, Fgf9) or female-associated (Fst, Foxl2, Wnt4) genes in germline GATA4–FOG2 mutants. These results also suggest that once the progenitor cells overcome the sex determination barrier, GATA4 is no longer required for the global regulation of Sertoli cell genes. Sox9, Mis, and Dhh are expressed normally in the absence of GATA4 in the Sertoli cells of the testis. Instead, GATA4 appears to have a more limited function in testis differentiation regulating a specific subset of genes in the Sertoli cells, with Dmrt1 being a prime example (Fig. 4.4). Importantly, this later GATA4 function is no less critical for normal testis development, as the male differentiation program in postnatal GATA4SF mutants ultimately collapsed. In many respects, loss of Dmrt1 expression in the Sertoli cells of the GATA4SF mutants is particularly insightful as it occurs in the context of an otherwise apparently normally developing Sertoli cell. DMRT1 expression is exclusive to the developing gonads where it is expressed in Sertoli cells of the testis as well as in germ cells in both sexes. In humans, DMRT1 is implicated in

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GATA4 Sox9 Mis Dhh Fgf9

SOX9 MIS DHH FGF9

Dmrt1 Cst9 Clu

Figure 4.4. GATA4 (early and late) gene regulation in the testis. Prior to the establishment of the male sex determination pathway, GATA4 is required to achieve threshold level of Sry expression in pre-Sertoli cells. In the pre-Sertoli cell, GATA4 is also an integral participant in the activation of several male genes required for testis differentiation, namely Sox9, Amh/Mis, Dhh, and Fgf9. Once the fate of Sertoli cells is determined, GATA4 is no longer required for the maintenance of this expression but is responsible instead for the regulation of another set of “late” male genes including Dmrt1, Cst9, and Clu.

embryonic testis development and sex determination (Raymond et al., 1999; reviewed in Ottolenghi and McElreavey, 2000), while in mice, it appears to be essential only after the time of birth (Raymond et al., 2000). Conditional targeting revealed separate requirements for mDMRT1 in Sertoli cell postnatal differentiation and in promoting germ cell radial migration to the tubule periphery, their mitotic reactivation, and viability (Kim et al., 2007a). Recent reports from the Zarkower laboratory document the mechanism of Dmrt1 action in fetal germ cells and adult spermatogenesis (Krentz et al., 2009; Matson et al., 2010). Dmrt1 expression is lost from the Sertoli cells of GATA4SF and Wt1_CreERT2; Gata4fl/fl mutants (Manuylov et al., 2011). The overproliferation of Sertoli cells in GATA4 mutants (Manuylov et al., 2011) strongly resembles that observed in postnatal Dmrt1/ testis previously (Raymond et al., 2000). As the testis cord defect in the GATA4 mutants is manifested considerably earlier (i.e., during embryogenesis), it cannot be attributed solely to the loss of Dmrt1 expression. While it is possible that a phenotype in GATA4SF mutants involves downregulation of other Dmrt genes in addition to Dmrt1, this possibility is unlikely, as their expression in the developing testis is already low. Microarray analysis identified a number of genes (e.g., Clu (clusterin) and Cys9 (cystatin 9)) that are downregulated upon GATA4 loss as early as E14.5 (Manuylov et al., 2011). Deregulated expression of these and other genes in addition to Dmrt1 is likely a contributing factor to an earlier phenotype in GATA4SF mutants. In contrast to GATA4SF testis, the remaining Sertoli cells in the XY FOG2SF mutants retain DMRT1 expression that is comparable to that in the control testis. These data demonstrate that FOG2 is not required for male-specific DMRT1 expression and support the conclusion that upon sex determination, the functions of GATA4 and FOG2 proteins diverge (see also below).

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The control region of Dmrt1 contributing to Sertoli cell-specific transcriptional activity was characterized biochemically in primary cultures of rat Sertoli cells. The DNA fragment situated between  3.2 and  2.8 kb from the start site of rat Dmrt1 harbored several GATA sites that were preferentially recognized by GATA4 (Lei and Heckert, 2004). Dmrt1 regulatory cis-elements controlled by GATA4 were subsequently examined in transgenic mice where the  3.2 kb fragment appeared to be sufficient for guiding reporter expression to Sertoli cells (Lei et al., 2009). It is intriguing that this regulatory element is not conserved in mammals (Tevosian, Sergei, unpublished). Sf1Cre was documented to recombine only partially in the cells of CE (Bingham et al., 2006; Kim et al., 2007b; Manuylov et al., 2008), and GATA4 expression in these gonadal cells remained strong in GATA4SF mutants. These cells do not express Sertoli cell markers; nonetheless, they harbor doubly positive cells (SF1þ; WT1þ) that earlier in development contribute to the progenitor somatic cell population in the gonad (Karl and Capel, 1998). The role of the CE cell population in the testis post E12.5 is not understood, but their possible input necessitates a more nuanced interpretation of the outcomes in the Sf1Cre-generated gonadal phenotypes. In this respect, equivalent results were obtained with Wt1CreERT2 induced at E11.5 (with efficient deletion of Gata4 in coelomic cells) further strengthening the conclusion that the GATA4 loss-of-function phenotype is not influenced by residual GATA4 in CE cells. Gata4 gene excision using inducible Wt1CreERT2 also reinforced the conclusion that the specter of GATA4-regulated genes critically depends on the timing of gene loss. When excision is induced at E11.5, the resulting phenotype is indistinguishable from the Sf1Cre deletion as described above. In contrast, induced just a day earlier at E10.5, loss of Gata4 leads to an acute block in Sertoli cell gene expression, as well as an arrest in testis cord formation and male differentiation. These XY animals also express Foxl2, a marker of ovarian differentiation, in their gonads. In summary, earlier (presumably coinciding with the time when sex determination takes place) loss of GATA4 expression results in a more profound block in testis development, underscoring a dynamic role for this protein in gonadogenesis. GATA4 function is also required for the organization and correct partition of testis cords into homogeneous units. Gonadal loss of GATA4 early upon sex determination leads to a distinctive defect in cord structures that is most prominently presented in late embryogenesis. While surplus Sertoli cells that populate the cord interiors in GATA4 mutants are also present in postnatal Dmrt1-null testis, the highly irregular asymmetrical cord structures in GATA4 mutants do not appear to be a part of the Dmrt1-null phenotype. In contrast to Sf1Cre; Gata4 mutants, conditional Sf1Cre; Fog2 deletion in the XY animals is more reminiscent of the previously described conventional mutants with disrupted GATA4–FOG2 interaction. Loss of FOG2 results in the

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decrease in Sertoli cell number with concomitant decrease in Sox9, Mis, and Dhh expression. Importantly, in contrast to the germline loss of Fog2 that demonstrates a comprehensive block in both fates, somatic precursor cells in XY Fog2 conditional mutants express ovarian-associated genes and undergo sex reversal. The competence of genetically male (XY) Sf1Cre; Fog2fl/fl mutants to undergo sex reversal is in agreement with the fact that ovarian program in Sf1Cre; Fog2 females is unperturbed. These females are fertile and have normal size litters (Efimenko et al., submitted for publication). These recent results provide further evidence that both proteins in GATA4–FOG2 complex are required for SPC fate determination. In contrast, shortly after sex determination, expression of most gonad-specific genes becomes independent of GATA4. The same gonadal genetic program breaks from its FOG2 dependence slightly later. However, unlike GATA4, FOG2 is likely dispensable for gonadal development once the sex determination stage is over.

E. Role of GATA4 and FOG2 proteins in Leydig cells Studies of Gata4 knock-in (Gata4ki/ki) fetuses have established that GATA4 is strictly required for Sertoli and fetal Leydig cell differentiation (Tevosian et al., 2002). However, as Leydig cell differentiation is known to depend on Sertoli cell-derived factors (e.g., Brennan et al., 2003; Yao et al., 2002), it remained unclear whether GATA4 has a cell autonomous role in adult or fetal Leydig cell development. The continuous presence of GATA4 in these cells, as well as in vitro studies support the argument that GATA4 plays a role in the differentiation and/or function of steroidogenic gonadal cells. Cotransfection experiments in cultured cells have shown that GATA4 can upregulate the expression of numerous genes involved in steroidogenesis, namely StAR (Hiroi et al., 2004a,b; Martin et al., 2011), P450c17 (Fluck and Miller, 2004; Shi et al., 2009), aromatase (Tremblay and Viger, 2001), and HSD3b2 (Martin et al., 2005). Many of these studies were performed in heterologous cells, and while indicative of the role for Gata4 in fetal or adult Leydig cells, they did not address this question directly. More compelling evidence supporting the cell-autonomous function for GATA4 specifically in fetal Leydig cells was provided by Bielinska et al. (2007). The authors analyzed the contribution of XY GATA4-null ES cells (ESCs) to testicular tissues and observed that these cells retained the capacity to differentiate into testicular interstitial fibroblasts but exhibited a cell autonomous defect in fetal Leydig cell differentiation. In contrast, gene ablation studies clearly demonstrate that GATA4 is dramatically diminished in both Sertoli and Leydig cells in the conditionally targeted (either by SF1Cre or by inducible Wt1Cre_ERT2) GATA4 testis as early as E12.5 (Manuylov et al., 2011). Despite the early loss of GATA4 expression in both cell types, markers of fetal Leydig cells are prominently

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expressed in the mutant testis throughout embryogenesis (Manuylov et al., 2011). The seeming discrepancy between these two studies is most easily reconciled by considering two separate stages in somatic cell development. The GATA4-null ESC’s contribution experiment is in agreement with the previously reported inability of SPCs lacking GATA4–FOG2 complex to produce sexually differentiated cell types (Manuylov et al., 2008; Tevosian et al., 2002). This is supported by the observation that in the same experiments, ES Gata4/ cells were also incapable of contributing to Sertoli lineage (Bielinska et al., 2007). Hence the parsimonious way to bring these observations together would be to conclude that temporary expression of GATA4 prior to E11.5 in the conditional knockout setting provides the opportunity to overcome the first step in the SPCs differentiation into the somatic (either Sertoli or Leydig) cells in the gonads. Once this step is completed, subsequent steroidogenic enzyme expression in fetal Leydig cells proceeds qualitatively as normal, in the absence of GATA4. Interestingly, despite a profound decrease in Dhh expression and Sertoli cell numbers, XY FOG2SF gonads similarly retain a fair amount of Leydig cell expression. This data is consistent with the notion that a very limited Sertoli cell function is sufficient to adequately support the fetal Leydig cell steroidogenic program.

F. GATA factors in postnatal ovary and differentiated ovarian cells Postnatal ovarian development can be characterized as a series of morphogenetic events resulting in the formation of mature follicles, the basic functional units of the ovary. GATA4 and GATA6 are the only GATA proteins expressed in postnatal ovaries. Gata4 appears to be the sole GATA family member that is specifically expressed in somatic cells, both at embryonic and at postembryonic stages. Its expression can be detected in the cells of ovarian surface epithelium (OSE), granulosa, and theca cells of various mammalian species, including humans. Although Gata4 expression is present in all types of follicles, the level of expression elevates during the transition of primordial into primary follicles and subsequent follicular growth. GATA4 can also be observed in functional corpora lutea, but its expression is reduced as cells of corpora lutea regress (Anttonen et al., 2003; Gillio-Meina et al., 2003; Heikinheimo et al., 1997; Laitinen et al., 2000; Lavoie et al., 2004; Vaskivuo et al., 2001; Viger et al., 1998). Gata6 is documented to be expressed in somatic cells as well as germ cells in the late fetal and early postnatal ovary. Gata6 expression largely overlaps with Gata4 in somatic cells of postnatal ovary and is also detectable in oocytes during different stages of postnatal development, including mature oocytes (Gillio-Meina et al., 2003; Heikinheimo et al., 1997; Laitinen et al., 2000; Lavoie et al., 2004).

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Both Gata4 and Gata6 homozygous knockout mutants are embryonic lethal due to failure in ventral morphogenesis and a block in endoderm differentiation, respectively (Kuo et al., 1997; Molkentin et al., 1997; Morrisey et al., 1998). These embryonic conditions preclude a thorough analysis of GATA4 and GATA6 function in postnatal ovaries in vivo. Nevertheless, various in vitro studies implicated both factors in the regulation of genes critical for ovarian differentiation or function. Among the first GATA target genes described in gonadal cells were two members of the transforming growth factor-b (TGF-b) family: Amh/Mis and Inhibin a (Inha). In postnatal ovaries, AMH/MIS is expressed by granulosa cells and controls the formation of primary follicles through inhibiting excessive follicular recruitment by follicle-stimulating hormone (FSH) (Visser et al., 2006). Several studies demonstrated that the Amh/Mis promoter harboring a conserved GATA element is a prospective downstream target of GATA4. Importantly, the regulation of Amh/Mis expression requires transcriptional cooperation with SF1 (Tremblay and Viger, 1999; Viger et al., 1998; Watanabe et al., 2000). In addition, in vitro transfection assays provided evidence that FOG2, a transcriptional cofactor of GATA, is able to counter the transactivation effect of GATA4 on Amh/Mis in granulosa cells (Anttonen et al., 2003). Given the fact that granulosa cells of growing follicles express FOG2, these findings suggest a potential role for FOG2 in coordinating GATA4 transcriptional regulation. Inhibins are heterodimer glycoproteins composed of an a-subunit and either bA (Inhibin A) or bB (Inhibin B) subunits. Produced by the granulosa and theca cells of the ovary, inhibins are involved in the control of pituitary FSH secretion (Luisi et al., 2005). Transient transfection experiments demonstrated that dominant negative GATA4 variants or mutations of GATA-binding sites in the Inha promoter attenuated TGF-b-induced gene activation. In GATA4deficient cells, TGF-b enhanced the expression of the Inha promoter only in the presence of exogenous GATA4 (Anttonen et al., 2006). It has been shown that the Inha promoter contains two GATA-binding motifs that can be activated by either GATA4 or GATA6 (Robert et al., 2006). Although definitive proof of redundancy between GATA4 and GATA6 factors is still lacking, the example of Inhibin a promoter regulation suggests that these proteins may have partially overlapping functions in regulating somatic cell-specific genes in the ovary. Studies in cultured cells demonstrated that GATA factors can bind and regulate promoter activity of steroidogenic genes, including steroidogenic acute regulatory protein (StAR), 17-hydroxysteroid dehydrogenase type 1 (Hsd17b1), cytochrome P450, family 11, subfamily A, polypeptide 1 (Cyp11a1), or cytochrome P450, family 19, subfamily A, polypeptide 1 (Aromatase) (Cyp19a1) (Brown et al., 2007; Cai et al., 2007; Hiroi et al., 2004a,b; Kwintkiewicz et al., 2007; Sher et al., 2007; Silverman et al., 1999, 2006; Stocco et al., 2007). Gonadotropin-releasing hormone is an important autocrine and paracrine factor

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regulating ovarian function through the gonadotropin-releasing hormone receptor (GnRHR). Promoter activity experiments in granulosa-luteal cell lines demonstrated that GATA motifs are involved in regulation of GnRHR gene transcription (Cheng et al., 2002). Whether all or any of these genes are under the control of GATA4 regulation in vivo remains to be determined. A precise balance between cell proliferation and decreased apoptosis is important for proper ovarian development. An alteration in this balance has been implicated in pathological conditions such as ovarian granulosa cell tumors (GCTs). GATA4 regulation of B-cell lymphoma 2 (Bcl2, the founding member of the family of apoptosis regulator proteins) and Cyclin D2 (Ccdn2, an important regulator of cell cycle) was studied by transactivation assays as well as by disrupting GATA4 function with dominant negative approaches in mouse and human GCT cell lines (Kyronlahti et al., 2008). While GATA4 overexpression upregulated and dominant negative GATA4 suppressed Bcl2 expression in GCT cells, the effects on Ccdn2 were negligible. These results revealed a previously unappreciated relationship between GATA4 and Bcl2 in mammalian granulosa cells and demonstrated that GATA4 can regulate granulosa cell survival by transactivating Bcl2 (Kyronlahti et al., 2008). In addition to GCTs, evidence suggests that loss of GATA4 and/or GATA6 function may lead to the development of serous and mucinous ovarian carcinomas. Both proteins are expressed in OSE but are frequently lost in ovarian cancer cells (Cai et al., 2009; Capo-chichi et al., 2003). As revealed by ChIP assays, histone H3 and H4 acetylation of the GATA4 (but not GATA6) locus is greatly decreased in cancer cells compared to GATA4 positive nontumor lines. At the same time, trace amounts of Gata6 mRNA could be detected in cancer cells, suggesting that Gata6 is not transcriptionally silenced and that the message could be suppressed by other mechanisms (Caslini et al., 2006). siRNA knockdown of GATA factors leads to the dedifferentiation of cultured cells as validated by the loss of epithelial cell markers such as Disabled-2 and Laminin. However, reexpression of GATA factors is not capable of inducing Disabled2 expression in tumor cells, suggesting that the dedifferentiation caused by loss of GATA factors is irreversible (Capo-chichi et al., 2003). Recent work also documents that heterozygous Gata6 knockout mice develop a propensity for increased preneoplastic changes and the formation of inclusion cysts, providing in vivo evidence of GATA factors’ contribution to ovarian cancer development (Cai et al., 2009). As many of the critical events in gonadal (especially ovarian) development could be realized only postnatally, it is informative to analyze the animals carrying mutant genes after the time of birth. Conditional targeting is the only genetic approach to evaluate the loss of GATA factors in the gonads due to the lethality of conventional knockouts. In the first publication that addressed this issue, the authors implemented transgenic mice expressing a tetracycline-inducible

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small interfering RNA against GATA4 (Thurisch et al., 2009). Although Gata4 expression was almost abolished in the ovary, the transgenic mice did not show a significant reduction in expression of prospective GATA4 targets such as StAR or Amh. Nevertheless, inhibition of Gata4 expression led to the formation of ovarian teratoma in 10% of females, supporting a role of GATA4 as a tumor suppressor in ovarian tissue (Thurisch et al., 2009). In a recent study by Kyronlahti et al., the authors generated transgenic mice where Gata4 deletion was limited to Amhr2positive cells (Kyronlahti et al., 2011b). Amhr2Cre-mediated recombination of Gata4 does not take place until follicles reach secondary and small antral stages, thus limiting the analysis to postnatal ovarian development and maintenance of its function. Analysis of Gata4 conditional mutants revealed severe ovarian phenotypes, including impaired fertility and the formation of ovarian cysts. The ovaries of gonadotropin-stimulated Gata4; Amhr2Cre mice release fewer oocytes and express less aromatase (Kyronlahti et al., 2011b). Altogether, the aforementioned findings support the idea that GATA proteins are crucial factors involved in the regulation of postnatal ovarian development and the maintenance of ovarian function.

VI. CONCLUSIONS A recurring question in understanding gene expression is how a specific DNAbinding factor “decides” when and where to regulate unrelated sets of genes. This is especially pertinent for developing embryonic organs, with their rapidly changing milieu of interacting cells and evolving cellular lineages. GATA proteins are representative of this challenge that faces transcription factors given a diverse range of cells and organs where GATAs are called upon to regulate vastly unrelated tissue-specific genes. In addition to their reproductive function, the versatile GATA4 and its partner FOG2 are also an obligatory part of the developing cardiac system where the loss of GATA4 results in early lethality, well before the gonads arise. Not surprisingly, in most cases, it remains unclear whether or when a specific target gene is subjected to GATA-dependent regulation. Conditional gene targeting in mice has already made an invaluable contribution toward addressing these challenging questions and allowed defining the roster of genes that are controlled by GATA proteins in vivo. Mouse strains that express tissue-specific inducible Cre recombinases are successfully used to control the location as well as the timing of gene excision in the gonads. Also, strains carrying floxed versions of Gata6 (Sodhi et al., 2006) and Gata1 (Lindeboom et al., 2003) genes are available, making possible (although still arduous) simultaneous gene deletions to produce double or even triple knockouts. These studies are most certainly underway and will allow dissecting GATA proteins’ function in cells where expression of several GATA proteins overlaps.

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Further analysis of gonadal gene expression in these mutant animals will undoubtedly lead to the identification of additional GATA protein targets that were previously masked by the redundant expression. It is clear that GATA proteins cooperate with other transcription factors and signaling pathways to control gonadal development and gene expression. To complicate the matters, GATA proteins also regulate the expression of some of the key players in these pathways. In this respect, experiments that reintroduce some of these downstream target genes back in the GATA mutant animals under promoters that do not require GATA activation (rescue) will be instrumental in revealing the specific impact of these molecules on gonadal function and gene regulation. While Sertoli and granulosa cell differentiation strictly requires GATA4–FOG2 complex, this partnership is dissolved once sex determination stage is completed. A more acute gonadal phenotype upon Fog2 (vs. Gata4) loss may be attributed to concentration sensitivity; FOG2 level is likely to be limiting in the formation of the GATA4–FOG2 complex during sexual determination (Bouma et al., 2007b; Manuylov et al., 2007). The GATA-independent role of FOG2 could not be excluded (Hyun et al., 2009); however, a preponderance of evidence limits FOG1/2 roles to modulating GATA activities. Subsequent to the sex determination stage, gonadal development in both sexes appears to proceed as normal in the absence of Fog2 gene. In contrast, GATA4 remains essential for regulating organ morphogenesis and gene expression in the differentiated cells of testis and ovaries (Kyronlahti et al., 2011a,b; Manuylov et al., 2011). We expect that future work will confirm some of the prospective downstream GATA targets previously identified by cell culture studies. It is also likely that these in vivo experiments will allow for a more nuanced understanding of GATA control: some genes may require a constant GATA presence, while other regulatory elements will rely on GATA recruitment for either initiation or maintenance only.

Acknowledgment This work was supported by the NIH grant to SGT (HD042751).

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