Steroidogenic Factor 1
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The steroidogenic factor 1 (SF-1)
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
is a
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
involved in sex determination by controlling activity of genes related to the reproductive glands or
gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces ...
s and
adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex w ...
s. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding
cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...
steroid hydroxylases, however, further roles in endocrine function have since been discovered.


Structure

The ''NR5A1'' gene encodes a 461-amino acid protein that shares several conserved domains consistent with members of the nuclear receptor subfamily. The N-terminal domain includes two zinc fingers and is responsible for DNA binding via specific recognition of target sequences. Variations of AGGTCA DNA motifs allows SF-1 to interact with the major groove of the DNA helix and monomerically bind. Following binding, trans-activation of target genes depends on recruitment of co-activators such as
SRC-1 The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by l ...
,
GRIP1 GRIP1 may refer to: * Nuclear receptor coactivator 2 * GRIP1 (gene) * Glutamate receptor-interacting protein (GRIP) Glutamate receptor-interacting protein (GRIP) refers to either a family of proteins that bind to the glutamate receptor or specifica ...
,
PNRC The Philippine Red Cross (PRC; fil, Krus na Pula ng Pilipinas) is a non-profit humanitarian organization and a member of the International Red Cross and Red Crescent Movement. The PRC was established in 1947, with roots in the Philippine Rev ...
, or GCN5. Other critical domains of SF-1 include a proline-rich hinge region, ligand-binding domain, and a C-terminal activation domain for transcriptional interactions. A 30-amino acid extension of the DNA-binding domain known as the A-box stabilizes monomeric binding by acting as a DNA anchor. The hinge region can undergo post-transcriptional and translational modifications such as phosphorylation by cAMP-dependent kinase, that further enhance stability and transcriptional activity. SF-1 is considered an orphan receptor as high-affinity naturally occurring ligands have yet to be identified.


Homology

Analysis of mouse SF-1
cDNA In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a speci ...
revealed sequence similarities with
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many s ...
fushi tarazu A pair-rule gene is a type of gene involved in the development of the segmented embryos of insects. Pair-rule genes are expressed as a result of differing concentrations of gap gene proteins, which encode transcription factors controlling pair ...
factor I (FTZ-F1) which regulates the fushi tarazu
homeobox A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. For instance, mutations in a homeobox may change large-scale anatomical features of the full ...
gene. Several other FTZ-F1 homologs have been identified that implicate high level of
sequence conservation In evolutionary biology, conserved sequences are identical or similar Sequence (biology), sequences in nucleic acids (DNA sequence, DNA and RNA) or peptide sequence, proteins across species (homology (biology)#Orthology, orthologous sequences), ...
among vertebrates and invertebrates. For example, SF-1 cDNA shares an identical 1017 base-pair sequence with embryonal long terminal repeat-binding protein (ELP) cDNA isolated from embryonal carcinoma cells, differing only in their terminal ends.


Expression


Adult steroidogenic tissue

SF-1 expression is localized to adult steroidogenic tissues correlating with known expression profiles of steroid hydroxylases. Using ''in situ'' hybridization with SF-1 cRNA specific probe detected gene transcripts in adrenocortical cells, Leydig cells, and ovarian theca and granulosa cells. SF-1 specific antibody studies confirmed expression profile of SF-1 in rats and humans corresponding to sites of transcript detection.


Embryonic steroidogenic tissue

Genetic sex in mammals is determined by the presence or absence of the
Y chromosome The Y chromosome is one of two sex chromosomes ( allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or a ...
at fertilization. Sexually dimorphic development of embryonic gonads into testes or ovaries is activated by the SRY gene product. Sexual differentiation is then directed by hormones produced by embryonic testes, the presence of ovaries, or complete absence of gonads. SF-1 transcripts initially localize to the urogenital ridge before SF-1 expressing cells resolve into distinct adrenocortical and gonadal precursors that ultimately give rise to adrenal cortex and gonads. SF-1 transcripts precede the onset of SRY expression in the fetal testes hinting at gonadal developmental role. SRY influences the differentiation of the fetal testes into distinct compartments: testicular cords and interstitial region containing Leydig cells. Increase in SF-1 protein and detection in the steroidogenic Leydig cells and testicular cords coincides with development. However, in the ovaries, gonadal sexual differentiation is facilitated by reductions in SF-1 transcript and protein. SF-1 levels is strongly expressed at the onset of follicular development in
theca In biology, a theca (plural thecae) is a sheath or a covering. Botany In botany, the theca is related to plant's flower anatomy. The theca of an angiosperm consists of a pair of microsporangia that are adjacent to each other and share a commo ...
and granulosa cells which precedes expression of the
aromatase Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze ma ...
enzyme responsible for
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal a ...
biosynthesis.


Other sites

Embryonic mouse SF-1 transcripts have been discovered to localize within regions of the developing diencephalon and subsequently in the
ventromedial hypothalamic nucleus The ventromedial nucleus of the hypothalamus (VMN, also sometimes referred to as the ventromedial hypothalamus, VMH) is a nucleus of the hypothalamus. "The ventromedial hypothalamus (VMH) is a distinct morphological nucleus involved in terminatin ...
(VMH) suggesting roles beyond steroidogenic maintenance.
RT-PCR Reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique combining reverse transcription of RNA into DNA (in this context called complementary DNA or cDNA) and amplification of specific DNA targets using polymerase chai ...
approaches have detected transcripts of mice FTZ-F1 gene in the placenta and spleen; and SF-1 transcripts in the human placenta.


Post-translational Regulation

Transcription capacity of SF-1 can be influenced by post-translational modification. Specifically, phosphorylation of
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − for ...
203 is mediated by cyclin-dependent kinase 7. Mutations to CDK7 prevent interaction with the basal transcription factor, TFIIH, and formation of CDK-activating kinase complex. This inactivity has shown to repress phosphorylation of SF-1 and SF-1-dependent transcription.


Function

SF-1 is a critical regulator of reproduction, regulating the transcription of key genes involved in sexual development and reproduction, most notably
StAR A star is an astronomical object comprising a luminous spheroid of plasma held together by its gravity. The nearest star to Earth is the Sun. Many other stars are visible to the naked eye at night, but their immense distances from Earth make ...
and P450SCC. It can form a transcriptional complex with
TDF TDF may refer to: Rebel group * Tigray Defense Forces a rebel group situated in Tigray against the federal government. Defense force * Ukraine Territorial Defense Forces Technology * Tab delimited files, a tabular data file format * Tél ...
to up-regulate transcription of the
Sox9 Transcription factor SOX-9 is a protein that in humans is encoded by the ''SOX9'' gene. Function SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It is expressed by proliferating but n ...
gene. Its targets include
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s at every level of the hypothalamic-pituitary-gonadal axis, as well as many genes involved in gonadal and adrenal
steroidogenesis A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
. SF-1 has been identified as a transcriptional regulator for an array of different genes related to sex determination and differentiation,
reproduction Reproduction (or procreation or breeding) is the biological process by which new individual organisms – " offspring" – are produced from their "parent" or parents. Reproduction is a fundamental feature of all known life; each individual o ...
, and
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
via binding to their promoters. For example, SF-1 controls expression of '' Amh'' gene in
Sertoli cell Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-sti ...
s, whereby the presence or absence of the gene product affects development of Müllerian structures. Increased AMH protein levels leads to regression of such structures.
Leydig cell Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedra ...
s express SF-1 to regulate transcription of
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
ogenesis and
testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...
biosynthesis genes causing virilization in males.


Target Genes


Steroidogenic cells

First identified as a regulator of steroid hydroxylases within adrenocortical cells, studies aimed to define localization and expression of SF-1 have since revealed enzyme activity within other steroidogenic cells.


Sertoli cells

The Müllerian inhibiting substance (''MIS'' or ''AMH'') gene within Sertoli cells contains a conserved motif identical to the optimal binding sequence for SF-1. Gel mobility shift experiments and use of SF-1-specific
polyclonal antibodies Polyclonal antibodies (pAbs) are antibodies that are secreted by different B cell lineages within the body (whereas monoclonal antibodies come from a single cell lineage). They are a collection of immunoglobulin molecules that react against a sp ...
established binding complexes of SF-1 to MIS, however, other studies suggest the MIS promoter is repressed and not activated by SF-1 binding.


Gonadotropes

Gonadotrope-specific element, or GSE, in the promoter of the gene encoding α-subunit of
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as g ...
s (α-GSU) resembles the SF-1 binding sires. Studies have implicated SF-1 as an upstream regulator of a collection of genes required for gonadotrope function via GSE.


VMH

SF-1 knockout mice displayed profound defects in the VMH suggesting potential target genes at the site. Target genes have yet to be identified due to difficulties in studying gene expression in neurons.


SF-1 Gene Knockout

Several approaches used targeted gene disruption in mouse embryonic stem cells with the aim of identifying potential target genes of SF-1. The different targeting strategies include disruption to exons encoding for the zinc finger motif, disruption of a 3’-exon and targeted mutation of the initiator methionine. The corresponding observed phenotypic effects on endocrine development and function were found to be quite similar. Sf-1 knockout mice displayed diminished
corticosterone Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. It is of minor importance in humans, except in the very ra ...
levels while maintaining elevated
ACTH Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
levels. Observed morphological changes and DNA fragmentation was consistent with apoptosis and structural regression resulting in the death of all mice within 8 days after birth. Sf-1 function was determined to be necessary for development of primary steroidogenic tissue as evidenced by complete lack of adrenal and gonadal glands in the knockout. Male to female sex reversal of genitalia was also observed.


Clinical significance

Mutations in NR5A1 can produce intersex genitals, absence of puberty, and infertility. It is one cause of arrest of ovarian function in women <40 years of age, which occurs in 1% of all women.


Adrenal and gonadal failure

Two SF-1 variants associated with primary adrenal failure and complete gonadal dysgenesis have been reported as caused by ''NR5A1'' mutations. One reported case was found to have ''de novo''
heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
p.G35E change to the P-box domain. The affected region allows for DNA binding specificity through interactions with regulatory response elements of target genes. This p.G35E change may have a mild competitive or dominant negative effect on transactivation resulting in severe gonadal defects and adrenal dysfunction. Similarly,
homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
p.R92Q change within the A-box interfered with monomeric binding stability and reduced functional activity. This change requires mutations to both allele to display phenotypic effects as heterozygous carriers showed normal adrenal function.
Missense In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense ...
, in-frame and
frameshift mutation A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels (gene insertion, insertions or genetic deletion, deletions) of a number of nucleotides in a DNA sequence that is not divisible by ...
s of NR5A1 have been found in families with 46,XY
disorders of sex development Disorders of sex development (DSDs), also known as differences in sex development, diverse sex development and variations in sex characteristics (VSC), are congenital conditions affecting the reproductive system, in which development of chromos ...
, 46,XX
gonadal dysgenesis Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in the male or female. It is the atypical development of the gonads in an embryo, with reproductive tissue replaced with functionless, fibrous ti ...
and 46,XX
primary ovarian insufficiency Primary ovarian insufficiency (POI) (also called premature ovarian insufficiency, premature menopause, and premature ovarian failure) is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of fol ...
. 46,XY individuals may have ambiguous or female genitals. Individuals of either
karyotype A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...
may not enter puberty, although expression of the
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological prop ...
,
penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is ...
, fertility, and modes of inheritance can vary. Some mutations are dominant, some are
recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
.


46, XY disorders of sex development

Heterozygous ''NR5A1'' changes are emerging as a frequent contributor in 46, XY complete gonadal dysgenesis. In affected individuals, sexual development does not match their chromosomal makeup. Males, despite having 46, XY
karyotype A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...
, develop female external genitalia, as well as uterus and fallopian tubes, along with gonadal defects rendering them nonfunctional. ''NR5A1'' mutations have also been linked to partial gonadal dysgenesis, whereby affected individuals have ambiguous genitalia, urogenital sinus, absent or rudimentary Müllerian structures, and other abnormalities. Typically, these genetic changes are
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process c ...
,
nonsense Nonsense is a communication, via speech, writing, or any other symbolic system, that lacks any coherent meaning. Sometimes in ordinary usage, nonsense is synonymous with absurdity or the ridiculous. Many poets, novelists and songwriters have us ...
, or
missense In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense ...
mutations that alter DNA-binding and gene transcription. While many are ''de novo'', one-third of cases have been maternally inherited in a similar manner as
X-linked inheritance Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive ...
. Furthermore, one report of homozygous missense mutation p.D293N within the ligand-binding domain of SF-1 revealed
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
inheritance was also possible.


Infertility

Analysis of ''NR5A1'' in men with non-obstructive male factor infertility found those with gene changes had more severe forms of infertility and lower testosterone levels. These changes affected the hinge region of SF-1. It is important to note further studies are required to establish the relationship between SF-1 changes and infertility.


Additional Interactions

SF-1 has also been shown to interact with: *
Beta-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcri ...
* DAX1 *
NRIP1 Nuclear receptor-interacting protein 1 (NRIP1) also known as receptor-interacting protein 140 (RIP140) is a protein that in humans is encoded by the ''NRIP1'' gene. Function Nuclear receptor interacting protein 1 (NRIP1) is a nuclear prote ...
*
SOX9 Transcription factor SOX-9 is a protein that in humans is encoded by the ''SOX9'' gene. Function SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It is expressed by proliferating but n ...
* TRERF1.


References


Further reading

* * * * * * * * * * * * *


External links


GeneReviews/NCBI/NIH/UW entry on 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis OMIM entries on 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis
* {{Transcription factors, g2 Intracellular receptors 5