Vol. 10, No. 3
177
MINIREVIEW
The role of the orphan receptor SF-1
in the development and function
of the ovary
Jaroslaw Mlynarczuk1, Robert Rekawiecki
Institute of Animal Reproduction 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 involved in the regulation of reproductive processes. The SF-1 structure
is similar to that of the steroid receptors but does not have a modulatory
domain. The SF-1 as a transcription factor may interact with genes 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
Corresponding author: Intitute of Animal Reproduction and Food Research of Polish Academy
of Science, Tuwima 10, 10–747 Olsztyn, Poland, [email protected]
1
Copyright © 2010 by the Society for Biology of Reproduction
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nuclear receptors, and c/ by action as a monomer. During fetal development, the SF-1, is responsible for differentiation of the gonads and, during
the postnatal period, it is responsible for the increase in the expression
of genes involved in steroidogenesis. Knock-out of SF-1 gene leads to
a rapid death of newly born mice with symptoms of severe adrenal insufficiency. In humans, SF-1 dysfunction causes an adrenal insufficiency
and infertility. Learning of the SF-1 and other orphan receptors’ action
mechanisms, will allow the creation of specific drugs, helpful in preventing some diseases of the female reproductive tract. Reproductive Biology
2010 10 3: 177–193.
Key words: orphan receptors, SF-1 receptor, reproduction, ovaries.
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 gene expression
after activation by steroid and thyroid hormones, vitamin D and their derivatives, 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) receptors], there are numerous orphan receptors [20, 21]. Identification and function 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 – estrogenrelated 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].
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Nuclear receptors are classified into seven groups (NR0 - NR6) according
to their sequence homology 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 associate 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 hormone 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.
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SF-1 in the ovary
Figure 1. Classification of nuclear receptors. CAR: constitutive androgen receptor
[NR1I1]; COUP-TF: chicken ovoalbumin upstream promoter – transcription factor
[NR2F]; DAX-1: dosage-sensitive sex reversal, adrenal hypoplasia critical region
on chromosome X, gene 1 [NR0B1]; ERR: estrogen related receptor [NR3B];
PNR: photoreceptor cell-specific nuclear receptor [NR2E3]; PPAR: peroxisome
proliferator-activated receptor [NR1C], PXR: pregnane X receptor [NR1I2], ROR:
RAR-related orphan receptor [NR1F], RXR: retinoid X receptor [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 monooxygenase (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 protein 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 sequence similarity was observed between the SF-1 receptor in different mammals 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 function 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 ligand 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 activation 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 contains 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, dimerization site, activation function 2 sequence (AF-2) and cofactor binding 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
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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 transcriptional 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 composed 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 possess DBD domain and therefore cannot affect transcription in a typical
manner. It cannot be excluded that SF-1 may also undergo heterodimerization 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)] different from that of the dimer [69]. On the other hand, SF-1 monomer may
acquire the transcriptional activity after direct association with Sp1 protein
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Figure 3. Different pathways of SF-1 action in target genes. DAX-1: dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome 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 proteins: coactivators (e.g. GATA-4, SOX9) and corepressors (e.g.
NCOR2; fig. 4; [24, 61, 62]).
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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 chromosome 9 (locus q33) and encodes the protein of 461 amino acids [59].
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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 gonad 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
gene knockout died soon after birth with symptoms of adrenal cortex 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 aromatase 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 17alphahydroxylase/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
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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 oxytocin (NP-I/OT; fig. 4)
in bovine luteal and granulosa cells [31, 67]. SF-1 increased the transcription 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 estradiol 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 ovarian 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 effects of xenobiotics on SF-1 may also be responsible for numerous cases
of idiopathic infertility in humans and animals. Such a hypothesis is consistent 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 steroidogenesis in endometriosis [10, 40, 63].
Moreover, SF-1 may be used in the diagnosis of ovarian cancer, particularly in differential diagnosis of various types of tumors as well as in detecting 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 understanding 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.
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