Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

NR5a1

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101872

Synonyms

Historical Background

Steroidogenic factor 1 (SF-1), also called Adrenal 4 binding protein (Ad4BP), was originally discovered in the early 1990s by Drs. Parker and Morohashi as a regulator of steroid hydroxylases in adrenal glands (Lala et al. 1992; Morohashi et al. 1992). It is a transcription factor, member of the nuclear receptors superfamily. Official designation of the gene encoding for SF-1 is NR5a1, although in the literature the name SF-1 is still predominantly used, and therefore, we will use this designation throughout this chapter.

Numerous studies have shown wide role of SF-1 in the endocrine development and function beyond regulation of steroid hydroxylases. In particularly, studies with SF-1 knockout (SF-1 KO) mice have shown the importance of SF-1 for adrenal and gonadal development, development of the ventromedial nucleus of the hypothalamus (VMH), and spleen and pituitary gonadotropin-producing (gonadotrope) cells. Different studies have revealed that SF-1 does not regulate only the expression of genes encoding for steroid hydroxylases, but many other genes such as antimullerian hormone (AMH), gonadotropin-releasing hormone (GnRH) receptor, common alpha subunit of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), brain-derived neurotrophic factor (BDNF), and many others (reviewed in Schimmer and White 2010).

SF-1 Structure

SF-1 (NR5a1) gene resides on the chromosome 9 in humans and chromosome 2 in mice. Gene encodes for a protein that is 461 amino acids long in humans and 462 amino acids long in mice, and the gene is comprised of seven exons (Ninomiya et al. 1995). SF-1 protein is structured similarly to other nuclear hormone receptors. It has a modular domain structure with a zinc finger DNA-binding domain (DBD) at its N-terminal, a ligand-binding domain, AF-2 activation domain at its C-terminal, and an intervening proline-rich domain within hinge region. Within this proline-rich domain is also an AF-1-like region that has activational activity. Immediately proximately to the DBD lies an A box, also called fushi tarazu factor 1 box, which is believed to mediate specific binding of SF-1 protein to the hexamer target sequence of SF-1 (Schimmer and White 2010) (Fig. 1).
NR5a1, Fig. 1

Structure of SF-1 (NR5a1) gene (upper panel) and protein (lower panel); ZF zinc finger, DBD DNA-binding domain, LBD ligand-binding domain, R2 and R3 highly conserved regions within ligand-binding domain, AF activational domain; proline-rich region is within hinge region).

NR5a1, Fig. 2

Role of SF-1 in the development of the testis and male phenotype. Note that SF-1 is involved in all stages of male development, from bipotential gonad in the fetus to steroidogenesis in the adult testis.

Regulation of SF-1 Expression

Tissue-Specific Expression

In adult tissues, SF-1 is primarily expressed in steroidogenic cells such as adrenal cortex, testicular Leydig cells, ovarian theca, and granulosa cells and at lower levels in corpus luteum. However, SF-1 is also expressed at some other, non-steroidogenic cells and tissues such as testicular Sertoli cells, VMH, pituitary gonadotrope cells, and spleen. In the fetal tissues, SF-1 is initially expressed in the adrenal and gonadal primordia and serves as an early marker for developing gonads and adrenal glands. SF-1 is also expressed in the fetal spleen and in the prosencephalon, a region of developing brain that includes the hypothalamic primordium (Morohashi et al. 1995; Majdic and Saunders 1996; Hanley et al. 2000a).

Transcriptional Regulation of Expression

Regulation of SF-1 expression is not completely understood, yet. Proximal promoter of SF-1 gene contains SOX binding site, E-box, Sp1/Sp3 site, and CCAAT box (Nomura et al. 1995; Scherrer et al. 2002; Shen and Ingraham 2002). Further upstream and downstream, there are binding sites for other transcriptional regulators such as GATA-4, WT1, and Lhx9, and studies in vitro have shown a potential role of SOX15, SOX30, TEAD-4, and CBX2 proteins in the regulation of SF-1 expression. It is believed that variety of binding sites and transcriptional factors binding to the SF-1 promoter regions are needed to ensure tissue specificity of SF-1 expression (Schimmer and White 2010). However, in vivo studies have shown that these promoter regions are not sufficient to drive the full expression of SF-1 in all tissues that physiologically express this gene. A very large fragment of genomic DNA, flanking the Sf-1 gene is needed to recapitulate endogenous expression of SF-1 in GFP transgenic mice. This, about 5 KB long fragment extending from exon 2 of the Sf-1 gene into the upstream gene NR6A1 (germ cell nuclear factor, GCNF), is able to induce gene expression in Leydig cells, theca cells, VMH, and spleen, but not in the pituitary and corpus luteum (Stallings et al. 2002). Only large rat genomic fragment extending well into the NR6A1 and PSMB17 genes on either side of the Sf-1 gene duplicates patterns of Sf-1 endogenous expression (Karpova et al. 2005). Within this fragment, two conserved enhancer regions were identified that are required for the expression of Sf-1 in the VMH (Shima et al. 2005) and pituitary (Shima et al. 2008). In addition to specific enhancers for VMH and pituitary, special enhancer has been identified that drives the expression of SF-1 in the fetal adrenal gland. This enhancer is found within the intron 4 of the SF-1 gene and is necessary to sustain the expression of SF-1 in the fetal adrenal, but is insufficient to drive the expression of SF-1 in adult adrenal, suggesting that regulation in adult and fetal adrenal gland is differentially regulated (Zubair et al. 2006).

Epigenetic Regulation of SF-1 Expression

Several studies have shown the role of epigenetic regulation through the methylation of different sites within SF-1 regulatory regions playing a role in the expression of SF-1. The basal promoter of SF-1 contains 14 and 10 CpG islands in human and mouse, respectively. These CpG sites are spread across 250 bp and thus do not represent a classical CpG islands, but rather a weak CpG island, such that are frequently found in genes with high tissue specificity in their expression. Methylation pattern of SF-1 basal promoter is in nearly perfect correlation with the levels of expression with the exception of the pituitary, where basal promoter is hypermethylated, what is in agreement with the finding that expression in the pituitary is driven from alternative promoter.

Enhancers that drive tissue-specific expression of SF-1 in different tissues such as VMH, pituitary gonadotrope cells, and fetal adrenal all contain CpG sites, and methylation of these CpGs does follow expression patterns of SF-1 gene. Pituitary enhancer is thus hypomethylated in the pituitary gonadotrope cells and hypermethylated in the VMH neurons and adrenal cortex. Similarly, VMH enhancer is hypomethylated in VMH neurons but hypermethylated in adrenal glands and other tissues that do not use this enhancer for tissue-specific expression of SF-1. However, fetal adrenal specific enhancer is hypomethylated in fetal adrenal cells and remains hypomethylated in adult adrenals, despite solid evidence that this enhancer is not needed for adult adrenal expression (Hoivik et al. 2013).

SF-1 Function

Fetal Development of Gonads

During development, SF-1 expression is first detected in urogenital ridges of both sexes in murine fetuses at E9.5 (Ikeda et al. 1994; Morohashi et al. 1995) and in human fetuses at 32 days post-ovulation (Hanley et al. 2000b). In mice, total ablation of Sf-1 gene causes regression of the gonadal ridge by E11.5–12.0. The formation of the gonadal ridge is regulated also by other genes such as Emx2, Gata4, Wt1, Lhx9, Cbx, Pod1, Six1, and Six4 most of which are believed to act upstream of the Sf-1. Therefore it is not surprising that promotor region of Sf-1 gene contains binding sites for many of these genes and that impaired gonadal formation in mutant mouse fetuses for several of these genes is associated with downregulation or ectopic upregulation of the SF-1 (reviewed by Tanaka and Nishinakamura 2014).

Shift from the bipotential gonadal ridge to the testis happens in male mice fetuses around E10.5, triggered by the expression of Sry, which induces differentiation of somatic cells into Sertoli cells. SF-1 is proposed to be one of the initial upstream regulators of the Sry gene. A few hours later the control of the differentiation process is switched from Sry to Sox9. In Sertoli cells SF-1, together with Sox9, induces activation of the gene for AMH (Arango et al. 1999) and activates Cyp26b1, an enzyme that catalyzes degradation of the retinoic acid. AMH promotes the regression of Mullerian ducts, and the absence of retinoic acid prevents male germ cells from entering meiosis prematurely. In mice fetal Leydig cells appear in the interstitium around E12.5 and persist in the testis until approximately one week after birth, when adult fetal Leydig cells develop (O’Shaughnessy et al. 2006). SF-1 is expressed in fetal Leydig cells and remains expressed in adult Leydig cells, as it is needed for the production of androgens both during fetal development and in adulthood by regulating the expression of several steroidogenic enzymes (Parker and Schimmer 1997; Ikeda et al. 2001). It is still not known to what extend SF-1 regulates Leydig cell differentiation. While loss of one Sf-1 allele causes delayed Sertoli and Leydig cell differentiation, it does not impact the final number of adult Leydig cells (Luo et al. 1994; Park et al. 2005). However, conditional deletion of Sf-1 in testicular somatic cells result in the absence of fetal and adult Leydig and Sertoli cells in testes, but the absence of Leydig cells in this model could also be due to the absence of Sertoli cells (Jeyasuria et al. 2004). However, an ectopic upregulation of SF-1 in Pod1 lacZ/lacZ mice leads to remarkable increase in the number of fetal Leydig cells (Cui et al. 2004), suggesting direct involvement of SF-1 in the process of fetal Leydig cell formation.

In female mice fetuses, expression of SF-1 follows the same pattern as in males until E11.5–12.0. At E12.0 SF-1 transcripts are no longer detected in mouse developing ovaries, and its expression is switch on again just before birth (Ikeda et al. 1994; Morohashi et al. 1995; Majdic and Saunders 1996). In human ovaries downregulation of SF-1 is less striking. At 52 days post-ovulation, SF-1 remains broadly distributed through the ovaries, with stronger localization in the germinal epithelial layers, and SF-1 expression in the human fetus persists through the entire fetal development (Hanley et al. 2000b) (Fig. 2).

Fetal Development of Adrenals

In the developing adrenal glands, SF-1 transcripts are detected in mouse fetuses at E10.5 (Ikeda et al. 1994; Morohashi et al. 1995) and in humans at 33 days post-conception (Hanley et al. 2001). Besides SF-1, several other factors including WT1, Wnt-4, activin, Pbx1, and DAX-1 regulate adrenal development. Many of these interact directly with SF-1 (reviewed by Hammer et al. 2005), for example, WT1 together with Cited2 increase SF-1 expression (Val et al. 2007), while DAX1 was shown to repress SF-1 expression in developing adrenal cells (Ito et al. 1997; Zubair et al. 2006). Specific enhancer driving SF-1 expression in the fetal adrenal gland was identified in the fourth intron of the SF-1 gene and is called fetal adrenal enhancer (FAdE). FAdE is necessary for maintenance of adrenal progenitor cells in developing adrenal primordia (Fig. 3) (Zubair et al. 2006).
NR5a1, Fig. 3

SF-1 has a major role in the development of adrenal gland, together with WT1, Cited2, and Dax1, which are regulating SF-1 expression. The expression of SF-1 in the fetal adrenal gland is also auto regulated through the enhancer in intron 4 of SF-1 gene, called FAdE (fetal adrenal enhancer).

Gene dosage seems to play important role in the regulation of adrenal development by SF-1. In mice, heterozygous for disrupted Sf-1 allele (SF-1+/− mice), adrenals show a selective decrease in number of adrenal precursor cells at E10.0. Although by E13.5 cell proliferation increases, adrenals do not develop normally and are reduced in size in newborn mice (Bland et al. 2000a, 2004). While SF-1 haploinsufficiency results in the adrenal hypoplasia, overexpression of SF-1 in mice causes increased adrenal size and formation of ectopic adrenal cortical tissues in the thorax (Zubair et al. 2009).

Adult Steroidogenic Organs; Gonads and Adrenal Glands

In gonads and adrenal glands, SF-1 is a key regulator of steroid hormone biosynthesis. Control of steroid production already starts at the level of cholesterol transport. SF-1 increases the expression of the scavenger receptor B1 (SR-B1), important for cellular import of high-density lipoprotein cholesterol, and steroidogenic acute regulatory protein (StAR), which regulates transport of cholesterol from outer to inner mitochondrial membrane. SF-1 also regulates the expression of different cytochrome P450 steroid hydroxylases and other steroidogenic enzymes such as 3β-Hydroxysteroid dehydrogenase (HSD3B2 and HSD3B1) (Schimmer and White 2010). Transcription of enzymes involved in the steroid production in the adrenal cortex is primarily regulated by adrenocorticotropic hormone (ACTH) from the pituitary. After ACTH binds to its cognate receptor, the melanocortin 2 receptor (MC2-R), numerous signaling pathways are activated in adrenal cells and at least some of these pathways are believed to be regulated by SF-1 (Sewer and Waterman 2002). For example, activation of cAMP/PKA pathway, activated by ACTH, decreases the amount of sphingosine and lysosphingomyelin bound to SF-1. Both phospholipids act on SF-1 as inhibitory ligands, and reduced amount of both ligands increases the expression of P45017a -hydroxylase/17,20-lyase (CYP17A1), mediated by SF-1 (Urs et al. 2006).

In testicular Leydig cells, SF-1 regulates both basal and LH-stimulated production of testosterone through regulation of cytochrome P450 cholesterol side chain cleavage (CYP11A1), CYP17A1, HSD3B2, and also 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes (Schimmer and White 2010).

In ovaries, SF-1 is expressed in theca, granulosa, and luteal cells and has a role in production of estrogens during follicular phase, as well as in production of progesterone during luteal phase (Saxena et al. 2007).

Although initial studies reported that there is no deleterious phenotype in SF-1 +/− mice, subsequent studies did show the importance of gene dosage and that both alleles of Sf-1 gene are needed for normal development and function of adrenals (Bland et al. 2000a, b, 2004). Adrenal glands in SF-1 +/− mice are smaller, with normal zonation but marked cellular hypertrophy within the zona fasciculata and striking dilatation of the cortical vasculature. In SF-1 +/− mice stimulated plasma corticosterone levels are lower in comparison to WT mice, evening levels of ACTH are higher, and expression of StAR and MC2-R is increased, while, interestingly, expression of CYP11A1 expression is unchanged (Bland et al. 2000b).

Pituitary

SF-1 is expressed also in the anterior pituitary, specifically in gonadotrope cells (Ingraham et al. 1994; Shinoda et al. 1995). Global and pituitary-specific SF-1 KO mice have markedly diminished expression of LH, FSH, and receptor for GnRH suggesting that SF-1 regulates expression of these pituitary genes (Ingraham et al. 1994; Shinoda et al. 1995). This was confirmed by in vitro studies, demonstrating that SF-1 indeed regulates the expression of common α-subunit (αGSU) of LH and FSH, as well as β-subunits of both FSH and LH (βFSH and βLH), and GnRH receptor (Barnhart and Mellon 1994; Ingraham et al. 1994; Halvorson et al. 1996; Jacobs et al. 2003). However, it is not yet clear whether reduced expression of both LH and FSH in SF-1 KO mice is due to direct effect of missing Sf-1 gene or perhaps secondary due to diminished expression of GnRH receptor since expression of both LH and FSH is strongly influenced by GnRH, secreted from the hypothalamus. This is supported by finding that the treatment of SF-1 KO mice with supraphysiologic doses of GnRH stimulates LH and FSH production in the pituitary in SF-1 KO mice (Ikeda et al. 1995) indicating that gonadotropin cells are capable of gonadotropin synthesis in the absence of SF-1, although this was done only qualitatively (by immunohistochemistry and levels of expression were not determined).

Ventromedial Nucleus of the Hypothalamus

In the central nervous system, the VMH is the only part where SF-1 is expressed. In the mouse its expression has been detected in the hypothalamic primordium as early as embryonic day E9.0. Initial studies showed that target disruption of the gene encoding SF-1 impaired the cytoarchitecture of the VMH (Ikeda et al. 1995; Luo et al. 1995; Shinoda et al. 1995). Subsequent studies on SF-1 KO fetuses (E15) and neonates revealed that distribution of cells is altered significantly in the region of the developing VMH, but without significantly affecting cell numbers up until birth, suggesting that disrupted neuronal migration could be the main cause of disorganized VMH in SF-1 KO mice (Davis et al. 2004). SF-1 could be also required for terminal differentiation of the VMH and for expression of BDNF since SF-1 KO neonates show complete loss of projections to the bed nucleus of stria terminalis (BNST) and amygdala, and neuronal precursors do not express BDNF (Tran et al. 2003). Similar findings were reported in CNS-specific SF-1 KO mice, which have also diminished hypothalamic expression of BDNF, CRH type 2 receptor, and cannabinoid receptor 1 (CBR1) (Davis et al. 2004; Kim et al. 2008; Zhao et al. 2008).

In adult life, SF-1 KO mice develop obesity, caused mainly by hypoactivity rather than hyperphagia, suggesting the role of VMH in the regulation of spontaneous physical activity (Majdic et al. 2002). Expression of several orexigenic and anorexigenic peptides was studied in these mice, and although changes in their expression pattern were observed, this was most likely due to disrupted neuronal migration in the VMH region and might not be functionally connected with obese phenotype (Budefeld et al. 2011). Diminished running wheel activity was observed also in the CNS-specific SF-1 KO mice, although these mice only develop obesity when on high-fat diet, probably reflecting the difference between early and later disruption of the VMH development. In addition to the obesity when on high-fat diet, CNS-specific SF-1 KO mice have impaired thermogenesis after acute exposure to high-fat diet and have decreased expression of leptin receptors (LepR) in the VMH (Zhao et al. 2008; Kim et al. 2011).

VMH is also involved in the regulation of different social behaviors such as anxiety, aggression, defensive, maternal and female sexual behavior. CNS-specific SF-1 KO mice showed elevated anxiety (Zhao et al. 2008), impaired female sexual behavior – lordosis and subfertility with the decreased number of corpora lutea (Kim et al. 2010). Lordosis is also impaired in hormone primed agonadal SF-1 KO mice (Grgurevic et al. 2012), while in the absence of any hormones, these mice show elevated aggression toward receptive females (Grgurevic et al. 2008). In our laboratory we also noted elevated anxiety-like behavior and poorer parental behavior in global SF-1 KO mice when compared to WT mice (unpublished observations – Grgurevic), and our recent study shows that SF-1+/− females have impaired maternal behavior (Spanic et al. 2016). Study by DaSilva et al. (Silva et al. 2013) has also shown the involvement of SF-1 neurons in the dorsolateral VMH in fear response, although in this study SF-1 was only used as a marker for the VMH neurons and direct role of SF-1 protein in the regulation of fear response was not studied.

Although numerous behavioral effects have been observed in SF-1 KO mice, it is not known to what extent SF-1 directly influence these behavioral traits as many of those could arise due to impaired VMH structure, and SF-1 role might only be important during development of this nucleus. However, SF-1 might also have a direct role in the regulation of some of these behaviors as studies have shown the role of SF-1 in the regulation of expression of genes encoding for BDNF, CBR1, CRH type 2 receptor, and LepR (Schimmer and White 2010).

Spleen

In adult mice, rats, and humans, SF-1 protein was detected in the red pulp but not in the white pulp of spleen. Several immunoreactive cells were also found inside the venous sinuses, which are part of a unique vascular system of the spleen (Morohashi et al. 1999). SF-1 is required for normal spleen development in humans (Zangen et al. 2014) and in mice which after global SF-1 ablation show abnormality in spleen size and structure (Morohashi et al. 1995). A recent report described similar phenotype in a 46,XY girl with complete sex reversal and asplenia, but without primary adrenal insufficiency. Genetic analysis confirmed a homozygous SF-1 mutation (p. R103Q) which consequently decreased SF-1 transactivation of the TLX1, a transcription factor that is essential for spleen development (Zangen et al. 2014). As shown by studies in mice, TLX1 is likely a downstream target of SF-1 through which SF-1 influence development of the spleen by modulating retinoic acid signaling pathway (Fig. 4). On the other hand, mouse Polycomb gene M33, another important factor for spleen development, might be an upstream regulator of SF-1 as similar splenic phenotype as in SF-1 KO mice was found in M33 KO mice, and spleens from these mice have markedly reduced expression of SF-1 (Katoh-Fukui et al. 2005; Lenti et al. 2016).
NR5a1, Fig. 4

SF-1 influences spleen development by regulating expression of Tlx1 and Cyp26b1 genes. These two genes regulate spleen development through the repression of the retinoic acid signaling pathway (Rxr, Rar retinoic acid receptors, RA retinoic acid).

SF-1 in Human Disease

Based on in vitro and in vivo studies of SF-1, the first attempts to expose the potential roles of SF-1 in human pathology were focused on adrenal insufficiency and complete gonadal dysgenesis, a syndrome similar to SF-1 KO mice phenotype. This phenotype is very rare in humans; nevertheless, in 1999 Achermann et al. identified mutations in SF-1 in 46,XY girl with complete gonadal agenesis, male to female sex reversal, and primary adrenal failure. In this patient, de novo mutation (p. G35E) was found in the P-box of the first zinc finger domain, affecting key amino acid in this domain, responsible for DNA binding. The second patient had similar phenotype but was found to carry homozygous recessive mutation (p. R92Q) affecting key amino acid in the A box within the Ftz-F1 box. Despite these two mutations, it turned out that mutations in SF-1 are rare in patients with adrenal phenotype (Suntharalingham et al. 2015). In contrast, SF-1 seems to be more often involved in disorders of sexual development (DSD). Heterozygous mutations in SF-1 in DSD patients were found to be remarkably common, present in 10–20% of all DSD patients (Suntharalingham et al. 2015). The most often observed phenotype is a chromosomally male patient (46,XY DSD) with ambiguous genitalia and with, or more often without, Mullerian structures. The testes are often well developed, and main phenotype characteristics seem to be arising due to androgen deficiency. Therefore, in some cases, the patient may be misdiagnosed for androgen insensitivity syndrome (Coutant et al. 2007). In addition to 46,XY DSDs, SF-1 mutations have been identified in patients with hypospadias and undescended testes (Köhler et al. 2009) and bilateral anorchia (Philibert et al. 2007), and some studies suggested that mild mutations/variations in SF-1 gene might be involved in some cases of male factor infertility (Bashamboo et al. 2010; Röpke et al. 2013; Ferlin et al. 2015).

Similarly to male patients, primary ovarian insufficiency has been reported in sisters or mothers of children with DSD due to SF-1 mutations. The clinical phenotype in these patients is very variable, from rare reports of complete ovarian insufficiency and the absence of menarche to more common early menopause and early depletion of ovarian reserves (Janse et al. 2012; Voican et al. 2013).

Hyperactivity and/or overexpression of SF-1 has also been linked to pathologies in human patients. In high proportion of childhood adrenal carcinomas, duplication of the gene locus containing SF-1 gene has been reported in somatic cells, and overexpression of SF-1 has been detected in many adult adrenal tumors. The degree of overexpression of SF-1 might even be an important predictor of adrenal tumor outcome, as suggested by some studies (Almeida et al. 2010; Sbiera et al. 2010).

Interestingly, although studies in mice have shown importance of SF-1 also for the development of hypothalamus, no reports about SF-1 role in obesity in humans have been reported to date. Interestingly, there is one report suggesting a possible link between SF-1 mutations and psychiatric symptoms of anxiety and/or depression (Suwanai et al. 2013) although the direct connection between SF-1 mutations and psychiatric symptoms has not been unequivocally established.

Summary

SF-1, first identified over 20 years ago, has been shown conclusively to be one of the most important genes involved in the regulation of gonadal and adrenal development, with important functions in other tissues such as pituitary, hypothalamus, and spleen. Although some roles of SF-1 such as regulation of expression of steroidogenic enzymes in gonads and adrenal glands, regulation of expression of AMH and Sox9 in fetal Sertoli cells, regulation of GnRH receptor expression in the pituitary, and regulation of spleen development through Tlx1 and retinoic acid signaling have been clearly established, there are many questions still unanswered. Precise temporal and tissue-specific regulation of SF-1, functional role of the SF-1 in the hypothalamus, role of SF-1 in infertile patients, and some other human diseases are among the questions that are still not fully understood and will have to be studied in future years.

References

  1. Almeida MQ, Soares IC, Ribeiro TC, Fragoso MCB, Marins LV, Wakamatsu A, et al. Steroidogenic factor 1 overexpression and gene amplification are more frequent in adrenocortical tumors from children than from adults. J Clin Endocrinol Metabol. 2010;95(3):1458–62.CrossRefGoogle Scholar
  2. Arango NA, Lovell-Badge R, Behringer RR. Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell. 1999;99(4):409–19.PubMedCrossRefGoogle Scholar
  3. Barnhart KM, Mellon PL. The orphan nuclear receptor, steroidogenic factor-1, regulates the glycoprotein hormone alpha-subunit gene in pituitary gonadotropes. Mol Endocrinol. 1994;8(7):878–85.PubMedGoogle Scholar
  4. Bashamboo A, Ferraz-de-Souza B, Lourenço D, Lin L, Sebire NJ, Montjean D, et al. Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1. Am J Hum Genet. 2010;87(4):505–12.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bland ML, Jamieson C, Akana S, Dallman M, Ingraham HA. Gene dosage effects of steroidogenic factor 1 (SF-1) in adrenal development and the stress. Endocr Res. 2000a;26(4):515–6.PubMedCrossRefGoogle Scholar
  6. Bland ML, Jamieson CA, Akana SF, Bornstein SR, Eisenhofer G, Dallman MF, et al. Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response. Proc Natl Acad Sci U S A. 2000b;97(26):14488–93.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bland ML, Fowkes RC, Ingraham HA. Differential requirement for steroidogenic factor-1 gene dosage in adrenal development versus endocrine function. Mol Endocrinol. 2004;18(4):941–52.PubMedCrossRefGoogle Scholar
  8. Budefeld T, Tobet SA, Majdic G. Altered position of cell bodies and fibers in the ventromedial region in SF-1 knockout mice. Exp Neurol. 2011;232(2):176–84.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Coutant R, Mallet D, Lahlou N, Bouhours-Nouet N, Guichet AS, Coupris L, et al. Heterozygous mutation of steroidogenic factor-1 in 46, XY subjects may mimic partial androgen insensitivity syndrome. J Clin Endocrinolo Metabol. 2007;92(8):2868–73.CrossRefGoogle Scholar
  10. Cui S, Ross A, Stallings N, Parker KL, Capel B, Quaggin SE. Disrupted gonadogenesis and male-to-female sex reversal in Pod1 knockout mice. Development. 2004;131(16):4095–105.PubMedCrossRefGoogle Scholar
  11. Davis AM, Seney ML, Stallings NR, Zhao L, Parker KL, Tobet SA. Loss of steroidogenic factor 1 alters cellular topography in the mouse ventromedial nucleus of the hypothalamus. J Neurobiol. 2004;60(4):424–36.PubMedCrossRefGoogle Scholar
  12. Ferlin A, Santa Rocca M, Vinanzi C, Ghezzi M, Di Nisio A, Foresta C. Mutational screening of NR5A1 gene encoding steroidogenic factor 1 in cryptorchidism and male factor infertility and functional analysis of seven undescribed mutations. Fertil Steril. 2015;104(1):163–9. e1.Google Scholar
  13. Grgurevic N, Budefeld T, Rissman EF, Tobet SA, Majdic G. Aggressive behaviors in adult SF-1 knockout mice that are not exposed to gonadal steroids during development. Behav Neurosci. 2008;122(4):876–84.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Grgurevic N, Budefeld T, Spanic T, Tobet SA, Majdic G. Evidence that sex chromosome genes affect sexual differentiation of female sexual behavior. Horm Behav. 2012;61(5):719–24.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Halvorson LM, Kaiser UB, Chin WW. Stimulation of luteinizing hormone beta gene promoter activity by the orphan nuclear receptor, steroidogenic factor-1. J Biol Chem. 1996;271(12):6645–50.PubMedCrossRefGoogle Scholar
  16. Hammer GD, Parker KL, Schimmer BP. Minireview: transcriptional regulation of adrenocortical development. Endocrinology. 2005;146(3):1018–24.PubMedCrossRefGoogle Scholar
  17. Hanley NA, Hagan DM, Clement-Jones M, Ball SG, Strachan T, Salas-Cortes L, et al. SRY, SOX9, and DAX1 expression patterns during human sex determination and gonadal development. Mech Dev. 2000a;91(1/2):403–7.PubMedCrossRefGoogle Scholar
  18. Hanley NA, Ikeda Y, Luo X, Parker KL. Steroidogenic factor 1 (SF-1) is essential for ovarian development and function. Mol Cell Endocrinol. 2000b;163(1/2):27–32.PubMedCrossRefGoogle Scholar
  19. Hanley NA, Rainey WE, Wilson DI, Ball SG, Parker KL. Expression profiles of SF-1, DAX1, and CYP17 in the human fetal adrenal gland: potential interactions in gene regulation. Mol Endocrinol. 2001;15(1):57–68.PubMedCrossRefGoogle Scholar
  20. Hoivik EA, Bjanesoy TE, Bakke M. Epigenetic regulation of the gene encoding steroidogenic factor-1. Mol Cell Endocrinol. 2013;371(1):133–9.PubMedCrossRefGoogle Scholar
  21. Ikeda Y, Shen WH, Ingraham HA, Parker KL. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Mol Endocrinol. 1994;8(5):654–62.PubMedGoogle Scholar
  22. Ikeda Y, Luo X, Abbud R, Nilson JH, Parker KL. The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol Endocrinol. 1995;9(4):478–86.PubMedGoogle Scholar
  23. Ikeda Y, Takeda Y, Shikayama T, Mukai T, Hisano S, Morohashi KI. Comparative localization of Dax-1 and Ad4BP/SF-1 during development of the hypothalamic-pituitary-gonadal axis suggests their closely related and distinct functions. Dev Dyn. 2001;220(4):363–76.PubMedCrossRefGoogle Scholar
  24. Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH, Nachtigal MW, et al. The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev. 1994;8(19):2302–12.PubMedCrossRefGoogle Scholar
  25. Ito M, Yu R, Jameson JL. DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita. Mol Cell Biol. 1997;17(3):1476–83.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Jacobs SB, Coss D, McGillivray SM, Mellon PL. Nuclear factor Y and steroidogenic factor 1 physically and functionally interact to contribute to cell-specific expression of the mouse follicle-stimulating hormone-β gene. Mol Endocrinol. 2003;17(8):1470–83.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Janse F, Larissa M, Duran KJ, Kloosterman WP, Goverde AJ, Lambalk CB, et al. Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI). Fertil Steri. 2012;97(1):141–6. e2.Google Scholar
  28. Jeyasuria P, Ikeda Y, Jamin SP, Zhao L, De Rooij DG, Themmen AP, et al. Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function. Mol Endocrinol. 2004;18(7):1610–9.PubMedCrossRefGoogle Scholar
  29. Karpova T, Presley J, Manimaran RR, Scherrer SP, Tejada L, Peterson KR, et al. A FTZ-F1-containing yeast artificial chromosome recapitulates expression of steroidogenic factor 1 in vivo. Mol Endocrinol. 2005;19(10):2549–63.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Katoh-Fukui Y, Owaki A, Toyama Y, Kusaka M, Shinohara Y, Maekawa M, et al. Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression. Blood. 2005;106(5):1612–20.PubMedCrossRefGoogle Scholar
  31. Kim KW, Jo YH, Zhao L, Stallings NR, Chua Jr SC, Parker KL. Steroidogenic factor 1 regulates expression of the cannabinoid receptor 1 in the ventromedial hypothalamic nucleus. Mol Endocrinol. 2008;22(8):1950–61.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Kim KW, Li S, Zhao H, Peng B, Tobet SA, Elmquist JK, et al. CNS-specific ablation of steroidogenic factor 1 results in impaired female reproductive function. Mol Endocrinol. 2010;24(6):1240–50.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Kim KW, Zhao L, Donato Jr J, Kohno D, Xu Y, Elias CF, et al. Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. Proc Natl Acad Sci U S A. 2011;108(26):10673–8.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Köhler B, Lin L, Mazen I, Cetindag C, Biebermann H, Akkurt I, et al. The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46, XY males without adrenal insufficiency. Eur J Endocrinol. 2009;161(2):237–42.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Lala DS, Rice DA, Parker KL. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol Endocrinol. 1992;6(8):1249–58.PubMedGoogle Scholar
  36. Lenti E, Farinello D, Yokoyama KK, Penkov D, Castagnaro L, Lavorgna G, et al. Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development. J Clin Invest. 2016;126(7):2452–64.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell. 1994;77(4):481–90.PubMedCrossRefGoogle Scholar
  38. Luo X, Ikeda Y, Schlosser DA, Parker KL. Steroidogenic factor 1 is the essential transcript of the mouse Ftz-F1 gene. Mol Endocrinol. 1995;9(9):1233–9.PubMedGoogle Scholar
  39. Majdic G, Saunders PT. Differential patterns of expression of DAX-1 and steroidogenic factor-1 (SF-1) in the fetal rat testis. Endocrinology. 1996;137(8):3586–9.PubMedCrossRefGoogle Scholar
  40. Majdic G, Young M, Gomez-Sanchez E, Anderson P, Szczepaniak LS, Dobbins RL, et al. Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity. Endocrinology. 2002;143(2):607–14.PubMedCrossRefGoogle Scholar
  41. Morohashi K, Honda S, Inomata Y, Handa H, Omura T. A common trans-acting factor, Ad4-binding protein, to the promoters of steroidogenic P-450s. J Biol Chem. 1992;267(25):17913–9.PubMedGoogle Scholar
  42. Morohashi K, Hatano O, Nomura M, Takayama K, Hara M, Yoshii H, et al. Function and distribution of a steroidogenic cell-specific transcription factor, Ad4BP. J Steroid Biochem Mol Biol. 1995;53(1):81–8.PubMedCrossRefGoogle Scholar
  43. Morohashi K, Tsuboi-Asai H, Matsushita S, Suda M, Nakashima M, Sasano H, et al. Structural and functional abnormalities in the spleen of anmFtz-F1 gene–disrupted mouse. Blood. 1999;93(5):1586–94.PubMedGoogle Scholar
  44. Ninomiya Y, Okada M, Kotomura N, Suzuki K, Tsukiyama T, Niwa O. Genomic organization and isoforms of the mouse ELP gene. J Biochem (Tokyo). 1995;118(2):380–9.CrossRefGoogle Scholar
  45. Nomura M, Bärtsch S, Nawata H, Omura T, Morohashi K. An E box element is required for the expression of the ad4bp gene, a mammalian homologue of ftz-f1 gene, which is essential for adrenal and gonadal development. J Biol Chem. 1995;270(13):7453–61.PubMedCrossRefGoogle Scholar
  46. O’Shaughnessy PJ, Baker PJ, Johnston H. The foetal Leydig cell – differentiation, function and regulation. Int J Androl. 2006;29(1):90–5 .discussion 105-8PubMedCrossRefGoogle Scholar
  47. Park SY, Meeks JJ, Raverot G, Pfaff LE, Weiss J, Hammer GD, et al. Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development. Development. 2005;132(10):2415–23.PubMedCrossRefGoogle Scholar
  48. Parker KL, Schimmer BP. Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev. 1997;18(3):361–77.PubMedCrossRefGoogle Scholar
  49. Philibert P, Zenaty D, Lin L, Soskin S, Audran F, Léger J, et al. Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study. Hum Reprod. 2007;22(12):3255–61.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Röpke A, Tewes A-C, Gromoll J, Kliesch S, Wieacker P, Tüttelmann F. Comprehensive sequence analysis of the NR5A1 gene encoding steroidogenic factor 1 in a large group of infertile males. Eur J Hum Genet. 2013;21(9):1012–5.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Saxena D, Escamilla-Hernandez R, Little-Ihrig L, Zeleznik AJ. Liver receptor homolog-1 and steroidogenic factor-1 have similar actions on rat granulosa cell steroidogenesis. Endocrinology. 2007;148(2):726–34.PubMedCrossRefGoogle Scholar
  52. Sbiera S, Schmull S, Assie G, Voelker H-U, Kraus L, Beyer M, et al. High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J Clin Endocrinol Metabol. 2010;95(10):E161–E71.CrossRefGoogle Scholar
  53. Scherrer SP, Rice DA, Heckert LL. Expression of steroidogenic factor 1 in the testis requires an interactive array of elements within its proximal promoter. Biol Reprod. 2002;67(5):1509–21.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Schimmer BP, White PC. Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol Endocrinol. 2010;24(7):1322–37.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Sewer MB, Waterman MR. Adrenocorticotropin/cyclic adenosine 3′, 5′-monophosphate-mediated transcription of the human CYP17 gene in the adrenal cortex is dependent on phosphatase activity. Endocrinology. 2002;143(5):1769–77.PubMedCrossRefGoogle Scholar
  56. Shen JH, Ingraham HA. Regulation of the orphan nuclear receptor steroidogenic factor 1 by Sox proteins. Mol Endocrinol. 2002;16(3):529–40.PubMedCrossRefGoogle Scholar
  57. Shima Y, Zubair M, Ishihara S, Shinohara Y, Oka S, Kimura S, et al. Ventromedial hypothalamic nucleus-specific enhancer of Ad4BP/SF-1 gene. Mol Endocrinol. 2005;19(11):2812–23.PubMedCrossRefGoogle Scholar
  58. Shima Y, Zubair M, Komatsu T, Oka S, Yokoyama C, Tachibana T, et al. Pituitary homeobox 2 regulates adrenal4 binding protein/steroidogenic factor-1 gene transcription in the pituitary gonadotrope through interaction with the intronic enhancer. Mol Endocrinol. 2008;22(7):1633–46.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Shinoda K, Lei H, Yoshii H, Nomura M, Nagano M, Shiba H, et al. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn. 1995;204(1):22–9.PubMedCrossRefGoogle Scholar
  60. Silva BA, Mattucci C, Krzywkowski P, Murana E, Illarionova A, Grinevich V, et al. Independent hypothalamic circuits for social and predator fear. Nat Neurosci. 2013;16(12):1731–3.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Spanic T, Grgurevic N, Majdic G. Haploinsufficiency for steroidogenic factor 1 affects maternal behavior in mice. Front Behav Neurosci. 2016;10:131.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Stallings NR, Hanley NA, Majdic G, Zhao L, Bakke M, Parker KL. Development of a transgenic green fluorescent protein lineage marker for steroidogenic factor 1. Mol Endocrinol. 2002;16(10):2360–70.PubMedCrossRefGoogle Scholar
  63. Suntharalingham JP, Buonocore F, Duncan AJ, Achermann JC. DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015;29(4):607–19.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Suwanai AS, Ishii T, Haruna H, Yamataka A, Narumi S, Fukuzawa R, et al. A report of two novel NR5A1 mutation families: possible clinical phenotype of psychiatric symptoms of anxiety and/or depression. Clin Endocrinol. 2013;78(6):957–65.CrossRefGoogle Scholar
  65. Tanaka SS, Nishinakamura R. Regulation of male sex determination: genital ridge formation and Sry activation in mice. Cell Mol Life Sci. 2014;71(24):4781–802.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Tran PV, Lee MB, Marin O, Xu B, Jones KR, Reichardt LF, et al. Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons. Mol Cell Neurosci. 2003;22(4):441–53.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Urs AN, Dammer E, Sewer MB. Sphingosine regulates the transcription of CYP17 by binding to steroidogenic factor-1. Endocrinology. 2006;147(11):5249–58.PubMedCrossRefGoogle Scholar
  68. Val P, Martinez-Barbera J-P, Swain A. Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage. Development. 2007;134(12):2349–58.PubMedCrossRefGoogle Scholar
  69. Voican A, Bachelot A, Bouligand J, Francou B, Dulon J, Lombès M, et al. NR5A1 (SF-1) mutations are not a major cause of primary ovarian insufficiency. J Clin Endocrinol Metabol. 2013;98(5):E1017–E21.CrossRefGoogle Scholar
  70. Zangen D, Kaufman Y, Banne E, Weinberg-Shukron A, Abulibdeh A, Garfinkel BP, et al. Testicular differentiation factor SF-1 is required for human spleen development. J Clin Invest. 2014;124(5):2071–5.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Zhao L, Kim KW, Ikeda Y, Anderson KK, Beck L, Chase S, et al. Central nervous system-specific knockout of steroidogenic factor 1 results in increased anxiety-like behavior. Mol Endocrinol. 2008;22(6):1403–15.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Zubair M, Ishihara S, Oka S, Okumura K, Morohashi K. Two-step regulation of Ad4BP/SF-1 gene transcription during fetal adrenal development: initiation by a Hox-Pbx1-Prep1 complex and maintenance via autoregulation by Ad4BP/SF-1. Mol Cell Biol. 2006;26(11):4111–21.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Zubair M, Oka S, Parker KL, Morohashi K. Transgenic expression of Ad4BP/SF-1 in fetal adrenal progenitor cells leads to ectopic adrenal formation. Mol Endocrinol. 2009;23(10):1657–67.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Veterinary FacultyInstitute for Preclinical Sciences, University of LjubljanaLjubljanaSlovenia