Vol. 10, No. 3 177

MINIREVIEW

The role of the orphan SF-1 in the development and function of the

Jaroslaw Mlynarczuk1, Robert Rekawiecki

Institute of Animal and Food Research of Polish Academy of Science, Olsztyn, Poland

Received: 26 October 2009; accepted: 29 October 2010

SUMMARY

The development of oocyte and ovulation require a precise synchronization at systemic and local levels. Nuclear receptors are involved in the regulation of these processes. In addition to the well-known nuclear receptors (e.g. receptors for estradiol, progesterone, glucocorticoids), a group of “orphan receptors” are distinguished within a receptor family. The orphan receptors are characterized by a lack of defined physiological ligands. Steroidogenic Factor 1 (SF-1, NR5A1) is a member of the orphan receptor group and is in- volved in the regulation of reproductive processes. The SF-1 structure is similar to that of the receptors but does not have a modulatory domain. The SF-1 as a may interact with in three main ways: a/ by a mechanism typical for nuclear receptors, encompassing homodimerization of SF-1 units, b/ by a formation heterodimers with other

1Corresponding author: Intitute of Animal Reproduction and Food Research of Polish Academy of Science, Tuwima 10, 10–747 Olsztyn, Poland, [email protected]

Copyright © 2010 by the Society for Biology of Reproduction 178 SF-1 in the ovary nuclear receptors, and c/ by action as a monomer. During fetal develop- ment, the SF-1, is responsible for differentiation of the and, during the postnatal period, it is responsible for the increase in the expression of genes involved in steroidogenesis. Knock-out of SF-1 leads to a rapid death of newly born mice with symptoms of severe adrenal insuf- ficiency. In humans, SF-1 dysfunction causes an and infertility. Learning of the SF-1 and other orphan receptors’ action mechanisms, will allow the creation of specific drugs, helpful in prevent- ing some diseases of the female reproductive tract. Reproductive Biology 2010 10 3: 177–193. Key words: orphan receptors, SF-1 receptor, reproduction, .

INTRODUCTION

The main function of mammalian ovaries is the production of matured female gametes – oocytes. Development and maturation of oocytes is a multistage process which requires the timed action of many regulatory factors at both systemic and local levels. Nuclear receptors (NR), among other receptors, are engaged in the transmission of signals between cells. The NR superfamily of NR is a group of transcription factors which control the after activation by steroid and thyroid hormones, vitamin D and their deriva- tives, cholesterol and retinoic acid [37]. NR serves as an interface for signals from the whole body to a cell genome [58]. In addition to classical NR [e.g. steroid receptors, thyroid hormone (TR) receptors, vitamin D (VDR) recep- tors], there are numerous orphan receptors [20, 21]. Identification and func- tion of the latter was possible thanks to development of so-called reverse endocrinology [33]. Genes encoding unknown NR or putative response elements were determined during the mapping of the human and animal genomes. There are 48 NR in the human and 49 NR in the mouse genome [2, 41]. A natural ligand for the first discovered orphan receptor – - related receptor (ERRα; [21]) has not been identified yet. Experimental data indicates that many estrogenic substances (diethylstilbestrol, organochlorine pesticides, phytoestrogens) may be ligands of ERRα [2]. Mlynarczuk & Rekawiecki 179

Nuclear receptors are classified into seven groups (NR0 - NR6) according to their and phylogenetic relationships. Steroidogenic factor 1 (SF-1, AD4BP) is one of the NR family and belongs to the NR5 group and NR5A subgroup. Due to this and to the fact that SF-1 was the first receptor discovered in the subgroup, its official name is NR5A1. But its common name (SF-1) is also used in scientific literature. Another member of the NR5 group is liver receptor homologue-1 (LHR-1, NR5A2). The nuclear receptors are also classified according to their physiological ligands and potential function (fig. 1; [2]): 1. “endocrine” receptors: steroid hormone receptors, TR, VDR, retinoic acid receptors (RARs) characterized by high affinity for their ligands (Kd ≥ nM) and high transcriptional activity; 2. “true” orphan receptors: their physiological ligands are unknown, but they may have synthetic ligands. These receptors are often functional inhibitors of transcriptional activity of other NR however, it is unknown whether this inhibition is ligand-dependent or -independent [30]; 3. “adopted” orphan receptors: orphan receptors which were adopted after the discovery of their ligands. Compared to the endocrine receptors, these receptors are characterized by a lower affinity for their ligands and lower transcriptional activity. Within the adopted orphan receptor group, “enigmatic” orphan receptors were further distinguished. Some ligands of the enigmatic orphan receptors have been identified, but the nature of the ligand-dependent activation of these receptors is difficult to associ- ate with any physiological process. SF-1 is an example of an enigmatic orphan receptor with sphingosine as its natural ligand [64, 65]. The main pathway of SF-1 action is typical to that of endocrine receptors such as estradiol (ER) or progesterone (PR) receptors (fig. 3a). Steroid hor- mone receptors and other “endocrine” receptors diffuse through the plasma membrane of their target cells and bind to the specific NR subunits. Then, the ligand-activated subunits dimerize and acquire the transcriptional activity. Nuclear receptors may form homo- (dimerization of the same NR subunits) or heterodimers (dimerization of different NR subunits). After translocation to the nucleus, dimer binds to a specific hormone response element present in the promoter of a target gene and affects the gene’s transcription. 180 SF-1 in the ovary

Figure 1. Classification of nuclear receptors. CAR: constitutive [NR1I1]; COUP-TF: chicken ovoalbumin upstream promoter – transcription factor [NR2F]; DAX-1: dosage-sensitive sex reversal, adrenal hypoplasia critical region on X, gene 1 [NR0B1]; ERR: estrogen related receptor [NR3B]; PNR: photoreceptor cell-specific [NR2E3]; PPAR: peroxisome proliferator-activated receptor [NR1C], PXR: [NR1I2], ROR: RAR-related orphan receptor [NR1F], RXR: [NR2B], SF-1: steroidogenic factor-1 [NR5A1].

STRUCTURE OF SF- 1

The existence of SF-1 was predicted in 1984 after the identification of cDNA of bovine 21-hydroxylase and cholesterol side-chain cleavage monooxyge- nase (P450scc; [46, 68]). Two years later the response element for SF-1 was identified in the promoter region of the 21-hydroxylase gene [25, 52]. Next, the interacting with the response element for SF-1 was recognized [47, 54], SF-1 cDNA was cloned and the amino acid sequence of SF-1 protein was described [28]. SF-1 is a phylogenetic old structure. As high as 75–85% amino acid se- quence similarity was observed between the SF-1 receptor in different mam- mals and FTZ-F1, a SF-1 homolog discovered in Drosophilla melanogaster [56]. The SF-1 is functionally divided into three domains: DNA binding Mlynarczuk & Rekawiecki 181

Figure 2. Structure of SF-1 and classic nuclear receptor. AF-1/MD: activation func- tion sequence 1/modulatory domain; AF-2: activation function sequence-2; DBD: DNA binding domain, LBD: ligand binding domain; ZF1, ZF2: zinc fingers.

domain (DBD, region C), “hinge” region (flexible region, region D) and li- gand binding domain (LBD, region E; fig. 2). In contrast to other NR, SF-1 does not possess A/B region and its modulatory domain (MD) is extremely shortened (fig. 2). Hence, SF-1 does not have the ligand-independent activa- tion function 1 sequence (AF-1). However, the short MD present in SF-1 may be phosphorylated by MAP-kinases [19] and, thus, it may join cofactors (i.e. SOX9 or WT-1) affecting SF-1 transcriptional activity [16, 50]. The DNA binding domain is the most conserved part of SF-1. It con- tains DNA-binding motif composed of two zinc-chelating modules (zinc fingers) that coordinate the interaction between the receptor and hormone response element (HRE). The “hinge” region is partially responsible for homo- or heterodimerization. Miscellaneous cofactors may bind to this region and affect SF-1 transcriptional activity [60]. The ligand binding domain (LBD, domain E) is composed of a ligand binding pocket, di- merization site, activation function 2 sequence (AF-2) and cofactor bind- ing site. The domain mediates dimerization, ligand-induced activation as well as ligand-reversed transcriptional silencing. The enhancement of SF-1 transcriptional activity might be caused by Ptx-1 protein which binds to LBD domain [62]. Because SF-1 does not have a functional 182 SF-1 in the ovary domain A/B and AF-1 sequence (fig. 2), the activation of AF-2 sequence is sufficient for full transcriptional activity of the receptor [55]. In mice, three isoforms of SF-1 (ELP1– ELP3) were found as a result of mRNA SF-1 alternative splicing [51]. The existence of SF-1 isoforms was not confirmed in other mammals.

MECHANISM OF SF-1 ACTION

More than one pathway may be involved in the regulation of SF-1 tran- scriptional activity. The main pathway starts with the homodimerization of SF-1 units after ligand binding. This is followed by the activation of the transcription of genes containing promoters with the appropriate palindromic response elements [55]. The SF-1 response element is com- posed of two half-palindrome sequences: 5’-AGGTCANNNTGACCT-3’ [5]. Another pathway starts with the heterodimerization of SF-1 with other NR. These heterodimers may be formed by NR characterized by certain transcriptional activity (Retinoid X Receptors-RXR; 9-cis-Retinoid Acid Receptor-RAR) as well as by NR without such activity (DAX-1 of NR0 group; fig. 3bc). The heterodimers with transcriptionally active NR bind to direct repeats of half sites (5’-AGGTCANAGGTCA-3’) or reverted repeats (5’- GACCTNAGGTCA-3’; [3, 22]) and usually activate gene transcription. The heterodimers with transcriptionally inactive NR, i.e. NR0, usually inhibit transcriptional activity of SF-1 [30, 50]. NR0 receptors do not pos- sess DBD domain and therefore cannot affect transcription in a typical manner. It cannot be excluded that SF-1 may also undergo heterodimeriza- tion with steroid hormone receptors, e.g. ER. However, a physiological significance of such heterodimers has not yet been determined [34]. In addition, SF-1 may initiate a gene transcription as a monomer (a third pathway; fig. 3d) after prior phosphorylation of its residual MD domain through mitogen activated protein (MAP) kinases [53]. In such a case, the monomer binds to a sequence of DNA [(C/T)CAAGG(C/T)(A/G)] dif- ferent from that of the dimer [69]. On the other hand, SF-1 monomer may acquire the transcriptional activity after direct association with Sp1 protein Mlynarczuk & Rekawiecki 183

Figure 3. Different pathways of SF-1 action in target genes. DAX-1: dos- age-sensitive sex reversal, adrenal hypoplasia critical region, on chromo- some X gene 1 [NR0B1]; MAPK: MAP-kinase; RXR: retinoid X receptor [NR2B].

[38] and cAMP-responsive element binding protein. Next, the monomer is phosphorylated by MAP-kinases [11] which is followed by a binding to its half-palindromic site in a promoter region. The transcriptional activity of monomers and homo- or heterodimers may be regulated by numerous cofactor : coactivators (e.g. GATA-4, SOX9) and corepressors (e.g. NCOR2; fig. 4; [24, 61, 62]). 184 SF-1 in the ovary

Figure 4. General scheme presenting the regulation of SF-1 and cellular function of this receptor.

It is of interest that a specified response element may contain a response element sensitive to another nuclear receptor. For example, the ER response element (ERE) includes the response element which binds the orphan receptor EERα [72]. In some cases, response elements may overlap, e.g. the response element binding SF-1 may partially overlap with the response element sensitive to another orphan receptor: COUP-TFI (NR2F1 group). Such a case takes place in NP-I/OT gene in cattle [67].

SF-1 AND THE OVARY

Initially, SF-1 was found in steroidogenic cell lines and the cortex of adrenal glands (adrenal 4-binding protein; Ad4BP). In humans, SF-1 gene is located at ( q33) and encodes the protein of 461 amino acids [59]. Mlynarczuk & Rekawiecki 185

Gene and protein expressions of SF-1 were observed as early as in 9-day-old mouse embryos. During embryonic development, the largest amount of SF-1 protein was observed in cells from which reproductive organs develop [29]. In postnatal life, SF-1 was found in human, mouse and rat ovaries [16, 17, 26] as well as in bovine and equine ovarian cells [8, 49]. During early embryonic development, SF-1 activity is essential for sex differentiation and formation (fig. 4). Activation of SF-1 increases gene expression for the Müllerian inhibiting substance (MIS) [23] and MIS receptor in Sertoli cells, which results in Müllerian duct regression [39, 57, 74]. Transgenic mice without the SF-1 gene were born either without gonads or with immature gonads. Since SF-1 also controls development and differentiation of adrenal steroidogenic tissue, animals with the SF-1 died soon after birth with symptoms of failure [75]. The effect was not lethal in mice in which only gonadal activity of SF-1 was eradicated [32]. In these mice, however, transcription activity of Amhr2 gene, encoding a subtype of MIS receptor, was lost. The females were born with well-developed ovaries but were infertile; their ovaries contained few follicles and, sometimes, haemorrhagic cysts. When the follicles ovulated, corpora lutea were not formed. Similar symptoms were observed in mice with knockouts of ERα or genes [74]. SF-1 is also important for proper ovarian functioning in mature females. The receptor is involved in the regulation of ovarian steroidogenesis (fig. 4). In all the examined animals, except mice, the functional response element for SF-1 was identified in promoter of StAR gene [12, 42]. However, the manner in which SF-1 affects the expression of StAR gene is not fully recognized. It is known that the binding ability of SF-1 to its response element as well as the transcription activity of SF-1 with reference to the StAR gene may be regulated by DBD phosphorylation [12]. In addition to the StAR gene, SF-1 regulates transcriptional activity of other ovarian and adrenal genes i.e. P450scc, 3beta-hydroxysteroid dehydrogenase (3βHSD), steroid 17alpha- hydroxylase/17,20 lyase (P450c17), steroid 21-hydroxylase (P450c21), steroid 11-beta-hydroxylase (P450c11) and estrogen synthase (P450arom; [13, 28, 35, 43, 48, 71]). Moreover, SF-1 affects hormones and receptors involved in the systemic and local regulation of the ovarian cycle. This receptor 186 SF-1 in the ovary was reported to be a transcription factor for the inhibin-α gene in human granulosa cells [66] and for the precursor gene of (NP-I/OT; fig. 4) in bovine luteal and granulosa cells [31, 67]. SF-1 increased the transcrip- tion of the gonadotropin subunit α, LH subunit β and GnRH receptor genes in the mouse and bovine pituitary [3, 27]. Moreover, the response element for SF-1 was found in the promoter region of the SF-1 gene which suggests SF-1 self-regulation [17]. The expression of SF-1 gene is increased by estra- diol and gonadotropins in mice and rats, respectively [17, 26]. The number of possible ligand/SF-1/cofactor combinations is enormous, so quite often it is difficult to assess the real trigger of the transcription. The ability of SF-1 to affect the activity of many genes in the pituitary and ovary suggests its significant role in the regulation of reproductive processes. But presently many target genes for SF-1 are not known.

PATHOLOGICAL STATES ASSOCIATED WITH SF-1 DYSFUNCTION

Mutation in the hinge region of SF-1 in humans resulted in a change of arginine in position 225 to leucine and led to a failure in the secretory function of the adrenal cortex [7], whereas change of arginine in position 92 to glycine in the DBD domain resulted in adrenal cortex insufficiency and hermaphroditism. A mutated SF-1 may inhibit functions of normally built SF-1 [1, 14]. The previously published data suggests that SF-1 may be activated by a pesticide, atrazine [18]. Hence, it cannot be excluded that an increase in oxytocin (OT) secretion by bovine ovarian cells treated with polychlorina­ ted biphenyls (PCBs) and insecticides (DDT, DDE) is a result of an activation of SF-1 [44, 45]. Xenobiotic-derived activation of SF-1 may, in turn, trigger some unwanted changes in the auto- and paracrine regulation of the ovar- ian processes (e.g. increase in OT and inhibin secretion), and consequently, disturb the course of the ovarian cycle or pregnancy. There are certain clues which suggest the association of SF-1 dysfunction with polycystic ovary syndrome, ovulation disorders, luteinization and hormonal insufficiency Mlynarczuk & Rekawiecki 187 of corpus luteum as well as with ovarian cancers [32, 73]. More and more facts support the view that the local regulation of the ovarian function may be affected by actions of different environmental factors on SF-1. The ef- fects of xenobiotics on SF-1 may also be responsible for numerous cases of idiopathic infertility in humans and animals. Such a hypothesis is con- sistent with the fact that the frequency of spontaneous miscarriages was significantly higher in women with substantial amounts of PCBs and DDT in their tissues [4, 36]. In contrast to normal endometrium, the high expression of SF-1 mRNA was observed in endometriotic tissues [9]. These differences were associated with different levels of methylation of the SF-1 gene promoter. The SF-1 gene is heavily methylated in endometrial stromal cells, and it is unmethylated in endometriotic stromal cells [70]. These changes are often a consequence of long-term influence of some environmental pollutants [15]. Endometrio­ tic tissues as an additional source of steroid hormones and prostaglandins which is not submitted to gonadotropin regulation, may disturb the proper functioning of ovaries including ovulation [6]. Drugs acting as selective inhibitors of SF-1 activity, may be used as suppressors of the atypical ste- roidogenesis in endometriosis [10, 40, 63]. Moreover, SF-1 may be used in the diagnosis of ovarian cancer, particu- larly in differential diagnosis of various types of tumors as well as in de- tecting endometrioid alterations in women [9]. The overexpression of SF-1 is demonstrated only in ovarian neoplasms that originate from persistent fetal tissues [73] and in endometrioid lesions [9]. Research focused on SF-1 and other orphan receptor action mechanisms will allow the better under- standing of the regulation of ovarian function. In further perspective, this knowledge should help us to discover the etiology of some cases of idiopathic infertility and create new medicaments for their treatments.

ACKNOWLEDGEMENTS

The studies were supported by grant (0061/B/P01/2009/36) from Ministry of Science and Higher Education. 188 SF-1 in the ovary

REFERENCES

1. Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, Gurakan B, Jameson JL 2002 Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1 in a dose-dependent manner. Journal of Clinical En- docrinology and 87 1829–1833. 2. Barish GD, Downes M, Alaynick WA, Yu RT, Ocampo CB, Bookout AL, Mangelsdorf DJ, Evans RM 2005 A Nuclear Receptor Atlas: macrophage activation. Molecular Endocrinology 19 2466–2477. 3. Barnhart KM, Mellon PL 1994 The orphan nuclear receptor, SF-1, regulates the gly- coprotein hormone alpha-subunit in pituary gonadotropes. Molecular Endocrinology 8 878–885. 4. Beard J 2006 DDT and human health. Science of the Total Environment 355 78–89. 5. Beato M, Herrlich P, Schutz G 1995 Steroid hormone receptors: many actors in a search of a plot. Cell 83 851–857. 6. Benaglia L, Somigliana E, Vercellini P, Abbiati A, Ragni G, Fedele L 2009 Endometriotic ovarian cysts negatively affect the rate of spontaneous ovulation. Human Reproduction 24 2183–2186. 7. Biason-Lauber A, Schoenle EJ 2000 Apparently normal ovarian differentiation in a pre- pubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and ad- renocortical insufficiency. American Journal of Human Genetics 67 1563–1568. 8. Boerboom D, Pilon N, Behdjani R, Silversides DW, Sirois J 2000 Expression and regu- lation of transcripts encoding two members of the NR5A nuclear receptor subfamily of orphan nuclear receptors, steroidogenic factor-1 and NR5A2, in equine ovarian cells during the ovulatory process. Endocrinology 141 4647–4656. 9. Bulun SE, Utsonomija H, Lin Z, Yin P, Cheng YH, Pavone ME, Tukunaga H, Trukh- acheva E, Attar E, Gurates B, Milad MP, Confino E, Su E, Reierstad S, Xue Q 2009 Steroidogenic factor-1 and endometriosis. Molecular and Cellular Endocrinolology 300 104–108. 10. Bulun SE, Yang S, Fang Z, Gurates B, Tamura M, Zhou J, Sebastian S 2001 Role of aromatase in endometriotic disease. Journal of Steroid Biochemistry and Molecular Biology 79 19–25. 11. Carlone DL, Richards JS 1997 Functional interactions, phosphorylation, and levels of 3`,5`-cyclic adenosine monophosphate-regulatory element binding protein and ste- roidogenic factor-1 mediate hormone-regulated and constitutive expression of aromatase in gonadal cells. Molecular Endocrinology 11 292–304. 12. Christenson LK, Devoto L 2003 Cholesterol transport and steroidogenesis by the corpus luteum. Reproductive Biology and Endocrinology 1 90. 13. Clemens JW, Lala DS, Parker KL 1994 Steroidogenic factor 1 binding and transcrip- tional activity of the cholesterol side-chain cleavage promoter in rat granulosa cells. Endocrinology 134 1499–1508. 14. Correa RV, Domenice S, Bingham NC, Billerbeck AE, Rainey WE, Parker KL, Men- donca BB 2004 A microdeletion in the ligand binding domain of human steroidogenic Mlynarczuk & Rekawiecki 189

factor 1 causes XY sex reversal without adrenal insufficiency. Journal of Clinical Endocrinology and Metabolism 89 1767–1772. 15. Crews D, McLachlan JA 2006 Epigenetics, evolution endocrine disruption, health and disease. Endocrinology 147 S4-S10. 16. De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck R, Scherer G, Poulat F, Berta P 1998 Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene. Molecular and Cellular Biology 18 6653–6665. 17. Falender AE, Lanz R, Malenfant D, Belanger L, Richards JS 2003 Differential expres- sion of steroidogenic factor-1 and FTF/LRH-1 in the rodent ovary. Endocrinology 144 3598–3610. 18. Fan WQ, Yanase T, Morinaga H, Gondo S, Okabe T, Nomura M, Komatsu T, Morohashi K-I, Hayes TB, Takayanagi R, Nawata H 2007 Atrazine-induced aromatase expression is SF-1 dependent: implications for endocrine disruptions in wildlife and reproductive cancers in human. Environmental Health Perspectives 115 720–727. 19. Giguere V 1999 Orphan nuclear receptors: from gene to function. Endocrine Reviews 20 689–725. 20. Giguere V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G 1994 Isoform-specific amino-terminal domains dedicate DNA-binding properties of RORα , a novel family of orphan hormone nuclear receptors. Genes and Development 8 538–553. 21. Giguere V, Yang N, Segui P, Evans RM 1988 Identification of a new class of steroid hormone receptors. Nature 331 91–94. 22. Glass CK 1994 Differential recognitions of nuclear hormone receptors monomers, dimers, and heterodimers. Endocrine Reviews 15 391–407. 23. Guili G, Shen WH, Ingraham HA 1997 The nuclear receptor SF-1 mediates sexually dimorphic expression of müllerian inhibiting substance, in vivo. Development 124 1799–1807. 24. Hammer GD, Krylova I, Zhang Y, Darimont BD, Simpson K, Weigel NL, Ingraham HA 1999 Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruit- ments: integration of hormone signaling in reproduction and stress. Molecular Cell 3 521–526. 25. Handler JD, Schimmer BP, Flynn TR, Szyf M, Seidman JG, Parker KL 1988 An enhancer element and functional cAMP-dependent protein kinase are required for expression of adrenocortical 21-hydroxylase. Journal of Biological Chemistry 263 13068–13073. 26. Hinshelwood MM, Repa JJ, Shelton JM, Richardson JA, Mangelsdorf DJ, Mendelson CR 2003 Expression of LRH-1 and SF-1 in the mouse ovary: localization in different cell types correlates with differing function. Molecular and Cellular Endocrinology 207 39–45. 27. Holvorson LM, Kaiser UB, Chin WW 1996 Stimulation of luteinizing hormone β gene promoter activity by the orphan receptor, steroidogenic factor-1. Journal of Biological Chemistry 271 6645–6650. 28. Honda T, Morohashi KI, Nomura T, Takeya K, Kitajima M, Omura T 1993 Ad4BP regulating steroidogenic P450 gene is a member of steroid superfam- ily. Journal of Biological Chemistry 268 7494–7502. 190 SF-1 in the ovary

29. Ikeda Y, Shen WH, Ingraham HA, Parker KL 1994 Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Molecular Endocrinology 8 654–642. 30. Ito M, Yu R, Jameson JL 1997 DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal that is deleted in adrenal hypoplasia congenita. Molecular and Cel- lular Biology 13 1476–1483. 31. Ivell R, Bathgate R, Walther N 1999 Luteal peptides and their genes as important markers of gonadal differentiation. Journal of Reproduction and Fertility Supplement 54 207–216. 32. Jeyasuria P, Ikeda Y, Jasmin SP, Zhao L, De Rooij DG, Themmen AP, Behringer RR, Parker KL 2004 Cell-specific knockout steroidogenic factor 1 reveals its essential role in gonadal function. Molecular Endocrinology 18 1610–1619. 33. Kliewer SA, Lehmann JM, Wilson TM 1999 Orphan nuclear receptors: shifting endo- crinology into reverse. Science 284 757–760. 34. Ledrean Y, Liu D, Wong AOL, Xiong F, Hew CL 1996 Steroidogenic factor 1 and es- tradiol receptor act in synergism to regulate the expression of the salmon gonadotropin 11-beta subunit gene. Molecular Endocrinolology 10 217–229. 35. Leers-Sucheta S, Morohashi K, Mason J, Melner M 1997 Synergistic activation of the human type II 3βHSD/D5-D4 isomerase promoter by the transcriptional factor SF-1/Ad4BP and phorbol ester. Journal Biological Chemistry 272 7960–7967. 36. Leoni V, Fabiani L, Marinelli G, Pucetti G, Tarsitani GF, De Carolis A, Vescia N, Morini A, Aleandri V, Pozzi V 1989 PCB and other organochlorine compounds in blood of women with or without miscarriage: a hypothesis of correlation. Ecotoxicology and Environmental Safety 17 1–11. 37. Lipsett MB 1978 Reproductive Endocrinology, pp 80–92. Eds Yen SC, Jaffe RB. WB Saunders, Philadelphia, USA. 38. Liu Z, Simpson ER 1997 Steroidogenic factor 1 (SF-1) and SP1 are required for regula- tion of bovine CYP11A gene expression in bovine luteal cells. Molecular Endocrinology 11 127–137. 39. Luo X, Ikeda Y, Parker KL 1994 A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77 481–480. 40. Madoux F, Li X, Chase P, Zastrow G, Cameron MD, Conkright JJ, Griffin PR, Thacher S, Hodder P 2008 Potent, selective and penetrant inhibitors of SF-1 by functional uHTS. Molecular Pharmacology 73 1776–1784. 41. Maglich JM, Sluder A, Guan X, Shi Y, McKee DD, Carrick K, Kamdar K, Wilson TM, Moore JT 2001 Comparison of complete nuclear receptors sets from the human, Caenorhabditis elegans and Drosophilla genomes. Genome Biology 2B, http://genom- ebiology.com/2001/2/8/research/0029.1. 42. Manna PR, Dyson MT, Eubank DW, Clark BJ, Lalli E, Sassone-Corsi P, Zeleznik AJ, Stocco DM 2002 Regulatory of steroidogenesis and the steroidogenic acute protein by a member of the cAMP response-element binding protein family. Mololecular Endocrinology 16 184–199. 43. Michael MD, Kligore MW, Morohashi KI, Simpson ER 1995 Ad4BP/SF-1 regulates cAMP-induced transcription from the proximal promoter (PII) of the human aromatase P450 (CYP19) gene in ovary. Journal of Biological Chemistry 270 13561–13566. Mlynarczuk & Rekawiecki 191

44. Mlynarczuk J, Niewiadowska A, Kotwica J 2005 Polychlorinated biphenyls impaired FSH-stimulated the secretion of and oxytocin from bovine granulosa cells. Bulletin of Veterinary Institute in Pulawy 49 411–417. 45. Mlynarczuk J, Wrobel M, Kotwica J 2009 Influence of polychlorinated biphenyls (PCBs), dichlorodiphenylotrichloroethane (DDT), and its metabolite – dichlorodiphenylodichlo- roethylene (DDE) on mRNA expression of NP-I/OT and PGA, involved in oxytocin synthesis in bovine granulosa and luteal cells. Reproductive Toxicology 28 354–358. 46. Morohashi K, Fujii-Kuriyama Y, Okada Y, Sogawa K, Hirose T, Inayama S, Omura T 1984 Molecular cloning and nucleotide sequence of cDNA for mRNA of mitochon- drial cytochrome P-450(SCC) of bovine adrenal cortex. Proceedings of the National Academy of Sciences of the United States of America 81 4647–4651. 47. Morohashi KI, Honda S-I, Inomata Y, Handa H, Omura T 1992 A common trans-acting factor, Ad4-bindingprotein, to the promoters od steroidogenic P-450s. Journal of Bio- logical Chemistry 267 17913–17919. 48. Morohashi KI, Zanger AM, Honda SI, Hara M, Waterman MR, Omura T 1993 Activa- tion of CYP11A and CYP11B gene promoters by sterogenic, cell-specific transcription factor Ad4BP. Molecular Endocrinology 7 1196–1204. 49. Morohashi K, Iida H, Nomura M, Hatano O, Honda S, Tsukiyama T, Niwa O, Hara T, Takakusu A, Shibata Y 1994 Functional difference between Ad4BP and ELP, and their distributions in steroidogenic tissues. Molecular Endocrinology 8 643–653. 50. Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA 1998 Wilms’ tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.Cell 93 445–454. 51. Ninomiya Y, Okada M, Kotomura N, Suzuki T, Tsukiyama R, Niwa O 1995 Genomic organization and isoforms of the mouse ELP gene. Journal of Biochemistry 118 380– 389. 52. Parker KL, Schimmer BP, Chaplin DD, Deidman JG 1986 Characterization of a regula- tory region of the steroid 21-hydroxylase gene. Journal of Biological Chemistry 261 15353–15355. 53. Parker KL, Rice DA, Lala DS, Ikeda Y, Luo X, Bakke M, Zhao L, Frigieri C, Hanley NA, Stallings N, Schimmer BP 2002 Steroidogenic factor 1: an essential mediator of endocrine development. Recent Progress in Hormone Research 57 19–36. 54. Rice DA, Mouw AR, Bogerd A, Parker KL 1991 A shared promoter element regulates the expression of the steroid enzymes. Molecular Endocrinology 5 1552–1561. 55. Sadovsky Y, Crawford PA 1998 Developmental and physiologic roles of the nuclear receptor Steroidogenic Factor-I in the reproductive system. Journal of the Society for Gynecological Investigation 5 6–12. 56. Scott MP, Weiner AJ 1984 Structural relationship among genes that control development: sequence homology between the Antennapaedia, Ultrabithorax, and fushi tarazu loci of Drosophila. Proceedings of the National Academy of Sciences of the United States of America 81 4115–4119. 57. Shen WH, Moore CCD, Ikeda Y, Parker KL, Ingraham KA 1994 Nuclear receptor ste- roidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade. Cell 77 51–61. 192 SF-1 in the ovary

58. Sonoda J, Pei L, Evans RM 2008 Nuclear receptors: decoding metabolic disease. FEBS Letters 582 2–9. 59. Taketo M, Parker KL, Howard TA, Tsukiyama T, Wong M, Niwa O, Morton CC, Miron PM, Seldin MF 1995 Homolog of Drosophila Fushi-Tarazu factor 1 map to mouse chromosome 2 and human chromosome 9q33. Genomics 25 565–567. 60. Tan JA, Hall SH, Hamil KG, Grossman G, Petrusz P, French FS 2002 Protein inhibi- tors of activated STAT resemble scaffold attachment factors and function as interacting nuclear receptor coregulators. Journal of Biological Chemistry 277 16993–17001. 61. Tremblay JJ, Viger RS 1999 Transcription factor GATA-4 enhances Müllerian inhibit- ing substance gene transcription through a direct interaction with the nuclear receptor SF-1. Molecular Endocrinology 13 445–454. 62. Tremblay JJ, Marcil A, Gauthier Y, Drouin J 1999 Ptx1 regulates SF-1 activity by an interaction that mimics the role of the ligand-binding domain. EMBO Journal 18 3431–3441. 63. Tsai SJ, Wu MH, Lin CC, Sun HS, Chan HM 2001 Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells. Journal of Clinical Endocrinology and Metabolism 86 5765–5773. 64. Urs AN, Dammer E, Kelly S, Wang E, Merril Jr AH, Sewer MB 2007 Steroidogenic Factor-1 is a sphingolipid binding protein. Molecular and Cellular Endocrinology 265–266 174–174. 65. Urs AN, Dammer E, Sewer MB 2008 Sphingosine regulates the transcription of CYP17 by binding to steroidogenic factor-1. Endocrinology 147 5249–5258. 66. Weck J, Mayo KE 2006 Switching of NR5A proteins associated with the inhibin alpha-subunit gene promoter after activation of the gene in granulosa cells. Molecular Endocrinology 20 1090–1103. 67. Wehrenberg U, Ivell R, Jansen M, von Goedecke S, Walther N 1994 Two orphan receptors binding to common site are involved in the regulation of the oxytocin gene in the ovary. Proceedings of the National Academy of Sciences of the United States of America 91 1440–1444. 68. White PC, New MI, Dupont B 1984 Cloning and expression of cDNA encoding a bo- vine adrenal cytochrome P-450 specific for steroid 21-hydroxylation. Proceedings of the National Academy of Sciences of the United States of America 91 1986–1990. 69. Wilson TE, Fahrner TJ, Milbrandt J 1993 The orphan receptors NGFI-B and steroido- genic factor 1 establish monomer binding as a third paradigm of nuclear receptor DNA-interaction. Molecular and Cellular Biology 13 5794–5804. 70. Xue Q, Lin Z, Yin P, Milad MP, Cheng YH, Confino E, Reiestad S, Bulun SE2007 Tran- scriptional activation of steroidogenic factor-1 by hypomethylation of the 5’CpG island in endometriosis. Journal of Clinical Endocrinology and Metabolism 92 3261–3267. 71. Zhang P, Mellon SH 1996 The orphan nuclear receptor steroidogenic factor-1 regulates the cAMP mediated transcriptional activation of rat cytochrome P450c14 (17α-hydroxylase/c17–20 lyase). Molecular Endocrinology 10 147–158. 72. Zhang Z, Teng CT 2000 -related receptor α1 interacts with coactivator and constitutively activates the estrogen response elements of the human lactoferrin gene. Journal of Biological Chemistry 275 20837–20846. Mlynarczuk & Rekawiecki 193

73. Zhao C, Barner R, Vinh TN, McManus K, Dabbs D, Vang R 2008 SF-1 is a diagnosti- cally useful immunohistochemical marker and comparable to other sex cord-stromal tumor markers for the differential diagnosis of ovarian sertoli cells tumor. International Journal of Gynecological Pathology 27 507–514. 74. Zhao H, Li Z, Cooney AJ, Lan Z-J 2007 Orphan nuclear receptor function in the ovary. Frontiers in Bioscience 12 3398–3405. 75. Zhao L, Bakke M, Hanley NA, Majdic G, Stallings NR, Jeyasuria P, Parker KL 2004 Tissue-specific knockouts of steroidogenic factor 1. Molecular and Cellular Endocri- nology 215 89–94.