Steroidogenic factor 1: Difference between revisions
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The '''steroidogenic factor 1''' ('''SF-1''') [[protein]] is a [[transcription factor]] involved in [[Sex-determination system|sex determination]] by controlling activity of genes related to the reproductive glands or [[ | The '''steroidogenic factor 1''' ('''SF-1''') [[protein]] is a [[transcription factor]] involved in [[Sex-determination system|sex determination]] by controlling activity of genes related to the reproductive glands or [[gonad]]s and [[adrenal gland]]s.<ref>{{Cite web|url=https://ghr.nlm.nih.gov/gene/NR5A1#|title=NR5A1 gene|last=Reference|first=Genetics Home|website=Genetics Home Reference|language=en|access-date=2017-11-30}}</ref> This protein is encoded by the [[Nuclear receptor|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]] [[steroid hydroxylase]]s, however, further roles in endocrine function have since been discovered.<ref name="Parker_1997">{{cite journal | vauthors = Parker KL, Schimmer BP | title = Steroidogenic factor 1: a key determinant of endocrine development and function | journal = Endocrine Reviews | volume = 18 | issue = 3 | pages = 361–77 | date = June 1997 | pmid = 9183568 | doi = 10.1210/edrv.18.3.0301 }}</ref> | ||
==Structure == | ==Structure == | ||
The ''NR5A1'' gene encodes a 461-amino acid protein that shares several [[Conserved sequence|conserved]] domains consistent with members of the nuclear receptor subfamily.<ref name="Parker_1997" /> The N-terminal domain includes two zinc fingers and is responsible for DNA binding via specific recognition of target sequences. | The ''NR5A1'' gene encodes a 461-amino acid protein that shares several [[Conserved sequence|conserved]] domains consistent with members of the nuclear receptor subfamily.<ref name="Parker_1997" /> 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.<ref>{{cite journal | vauthors = Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM | title = The nuclear receptor superfamily: the second decade | journal = Cell | volume = 83 | issue = 6 | pages = 835–9 | date = December 1995 | pmid = 8521507 | doi=10.1016/0092-8674(95)90199-x}}</ref> Following binding, trans-activation of target genes depends on recruitment of co-activators such as [[Nuclear receptor coactivator 1|SRC-1]], [[GRIP1 (gene)|GRIP1]], [[PNRC1|PNRC]], or [[GCN5L2|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 [[Protein kinase A|cAMP-dependent kinase]], that further enhance stability and transcriptional activity.<ref>{{cite journal | vauthors = Honda S, Morohashi K, Nomura M, Takeya H, Kitajima M, Omura T | title = Ad4BP regulating steroidogenic P-450 gene is a member of steroid hormone receptor superfamily | journal = The Journal of Biological Chemistry | volume = 268 | issue = 10 | pages = 7494–502 | date = April 1993 | pmid = 8463279 }}</ref> | ||
SF-1 is considered an orphan receptor as high-affinity naturally occurring ligands have yet to be identified. | SF-1 is considered an orphan receptor as high-affinity naturally occurring ligands have yet to be identified. | ||
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=== Embryonic steroidogenic tissue === | === Embryonic steroidogenic tissue === | ||
Genetic sex in mammals is determined by the presence or absence of the [[Y chromosome]] at fertilization. Sexually dimorphic development of embryonic gonads into testes or ovaries is activated by the [[Testis-determining factor|SRY]] gene product.<ref name="EPE">{{cite web | url = https://embryo.asu.edu/pages/male-development-chromosomally-female-mice-transgenic-sry-gene-1991-peter-koopman-et-al | title = "Male Development of Chromosomally Female Mice Transgenic for Sry gene" (1991), by Peter Koopman, et al. {{!}} The Embryo Project Encyclopedia | website=embryo.asu.edu | access-date = 2017-11-30 }}</ref> | Genetic sex in mammals is determined by the presence or absence of the [[Y chromosome]] at fertilization. Sexually dimorphic development of embryonic gonads into testes or ovaries is activated by the [[Testis-determining factor|SRY]] gene product.<ref name="EPE">{{cite web | url = https://embryo.asu.edu/pages/male-development-chromosomally-female-mice-transgenic-sry-gene-1991-peter-koopman-et-al | title = "Male Development of Chromosomally Female Mice Transgenic for Sry gene" (1991), by Peter Koopman, et al. {{!}} The Embryo Project Encyclopedia | website=embryo.asu.edu | access-date = 2017-11-30 }}</ref> 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.<ref name="EPE" /> Increase in SF-1 protein and detection in the steroidogenic Leydig cells and testicular cords coincides with development. | 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.<ref name="EPE" /> Increase in SF-1 protein and detection in the steroidogenic Leydig cells and testicular cords coincides with development. | ||
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SF-1 is a critical regulator of reproduction, regulating the transcription of key genes involved in sexual development and reproduction, most notably [[Steroidogenic acute regulatory protein|StAR]] and [[Cholesterol side-chain cleavage enzyme|P450<sub>SCC</sub>]]. It can form a transcriptional complex with [[Testis determining factor|TDF]] to up-regulate transcription of the [[Sox9]] gene. Its targets include [[gene]]s at every level of the [[hypothalamic-pituitary-gonadal axis]], as well as many genes involved in [[gonadal]] and [[adrenal]] [[steroidogenesis]].<ref name="pmid15579738">{{cite journal | vauthors = Jameson JL | title = Of mice and men: The tale of steroidogenic factor-1 | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 12 | pages = 5927–9 | date = December 2004 | pmid = 15579738 | doi = 10.1210/jc.2004-2047 }}</ref> | SF-1 is a critical regulator of reproduction, regulating the transcription of key genes involved in sexual development and reproduction, most notably [[Steroidogenic acute regulatory protein|StAR]] and [[Cholesterol side-chain cleavage enzyme|P450<sub>SCC</sub>]]. It can form a transcriptional complex with [[Testis determining factor|TDF]] to up-regulate transcription of the [[Sox9]] gene. Its targets include [[gene]]s at every level of the [[hypothalamic-pituitary-gonadal axis]], as well as many genes involved in [[gonadal]] and [[adrenal]] [[steroidogenesis]].<ref name="pmid15579738">{{cite journal | vauthors = Jameson JL | title = Of mice and men: The tale of steroidogenic factor-1 | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 12 | pages = 5927–9 | date = December 2004 | pmid = 15579738 | doi = 10.1210/jc.2004-2047 }}</ref> | ||
SF-1 has been identified as a transcriptional regulator for an array of different genes related to sex determination and differentiation, [[reproduction]], and [[metabolism]] via binding to their promoters. For example, SF-1 controls expression of ''[[Anti-Müllerian hormone|Amh]]'' gene in [[Sertoli cell | SF-1 has been identified as a transcriptional regulator for an array of different genes related to sex determination and differentiation, [[reproduction]], and [[metabolism]] via binding to their promoters. For example, SF-1 controls expression of ''[[Anti-Müllerian hormone|Amh]]'' gene in [[Sertoli cell]]s, whereby the presence or absence of the gene product affects development of [[Paramesonephric duct|Müllerian structures]]. Increased AMH protein levels leads to regression of such structures.<ref name="Parker_1997" /> [[Leydig cell]]s express SF-1 to regulate transcription of [[steroid]]ogenesis and [[testosterone]] biosynthesis genes causing virilization in males. | ||
== Target Genes == | == Target Genes == | ||
| Line 46: | Line 46: | ||
!Cell/Tissue | !Cell/Tissue | ||
|- | |- | ||
| | |rP450scc | ||
|granulosa | |granulosa cells | ||
|- | |- | ||
| | |mP450scc | ||
|Y1 adrenocortical cells | |Y1 adrenocortical cells | ||
|- | |- | ||
| | |bOxytocin | ||
|ovary | |ovary | ||
|- | |- | ||
| | |mStAR | ||
|MA-10 | |MA-10 Leydig | ||
|} | |} | ||
=== Sertoli cells === | === Sertoli cells === | ||
The Müllerian inhibiting substance (''MIS'') 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]] established binding complexes of SF-1 to MIS<ref>{{cite journal | vauthors = Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA | title = Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade | journal = Cell | volume = 77 | issue = 5 | pages = 651–61 | date = June 1994 | pmid = 8205615 }}</ref> | The Müllerian inhibiting substance (''MIS'') 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]] established binding complexes of SF-1 to MIS,<ref>{{cite journal | vauthors = Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA | title = Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade | journal = Cell | volume = 77 | issue = 5 | pages = 651–61 | date = June 1994 | pmid = 8205615 | doi=10.1016/0092-8674(94)90050-7}}</ref> however, other studies suggest the MIS promoter is repressed and not activated by SF-1 binding. | ||
=== Gonadotropes === | === Gonadotropes === | ||
Gonadotrope-specific element, or GSE, in the promoter of the gene encoding α-subunit of [[ | Gonadotrope-specific element, or GSE, in the promoter of the gene encoding α-subunit of [[glycoprotein]]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.<ref>{{cite journal | vauthors = Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH, Nachtigal MW, Abbud R, Nilson JH, Parker KL | title = The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis | journal = Genes & Development | volume = 8 | issue = 19 | pages = 2302–12 | date = October 1994 | pmid = 7958897 | doi=10.1101/gad.8.19.2302}}</ref> | ||
=== VMH === | === VMH === | ||
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== SF-1 Gene Knockout == | == SF-1 Gene Knockout == | ||
Several approaches used [[Gene knockout|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 zing finger motif, disruption of a 3’-exon and targeted mutation of the initiator methionine. | Several approaches used [[Gene knockout|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 zing 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.<ref name="Parker_1997" /> | ||
Sf-1 knockout mice displayed diminished [[corticosterone]] levels while maintaining elevated [[ACTH]] 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.<ref>{{cite journal | vauthors = Luo X, Ikeda Y, Schlosser DA, Parker KL | title = Steroidogenic factor 1 is the essential transcript of the mouse Ftz-F1 gene | journal = Molecular Endocrinology | volume = 9 | issue = 9 | pages = 1233–9 | date = September 1995 | pmid = 7491115 | doi = 10.1210/mend.9.9.7491115 }}</ref> | Sf-1 knockout mice displayed diminished [[corticosterone]] levels while maintaining elevated [[ACTH]] 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.<ref>{{cite journal | vauthors = Luo X, Ikeda Y, Schlosser DA, Parker KL | title = Steroidogenic factor 1 is the essential transcript of the mouse Ftz-F1 gene | journal = Molecular Endocrinology | volume = 9 | issue = 9 | pages = 1233–9 | date = September 1995 | pmid = 7491115 | doi = 10.1210/mend.9.9.7491115 }}</ref> | ||
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. | 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.<ref>{{cite journal | vauthors = Luo X, Ikeda Y, Parker KL | title = A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation | journal = Cell | volume = 77 | issue = 4 | pages = 481–90 | date = May 1994 | pmid = 8187173 | doi=10.1016/0092-8674(94)90211-9}}</ref> | ||
== Clinical significance == | == 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. | 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 === | ===Adrenal and gonadal failure === | ||
Two SF-1 variants associated with primary adrenal failure and [[Gonadal dysgenesis|complete gonadal dysgenesis]] have been reported as caused by ''NR5A1'' mutations. One reported case was found to have ''de novo'' [[Zygosity|heterozygous]] p.G35E change to the P-box domain.<ref name="Ferraz-de-Souza_2011">{{cite journal | vauthors = Ferraz-de-Souza B, Lin L, Achermann JC | title = Steroidogenic factor-1 (SF-1, NR5A1) and human disease | journal = Molecular and Cellular Endocrinology | volume = 336 | issue = 1-2 | pages = 198–205 | date = April 2011 | pmid = 21078366 | pmc = 3057017 | doi = 10.1016/j.mce.2010.11.006 }}</ref> 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, [[Zygosity|homozygous]] p.R92Q change within the A-box interfered with monomeric binding stability and reduced functional activity.<ref name="Ferraz-de-Souza_2011" /> This change requires mutations to both allele to display phenotypic effects as heterozygous carriers showed normal adrenal function. | Two SF-1 variants associated with primary adrenal failure and [[Gonadal dysgenesis|complete gonadal dysgenesis]] have been reported as caused by ''NR5A1'' mutations. One reported case was found to have ''de novo'' [[Zygosity|heterozygous]] p.G35E change to the P-box domain.<ref name="Ferraz-de-Souza_2011">{{cite journal | vauthors = Ferraz-de-Souza B, Lin L, Achermann JC | title = Steroidogenic factor-1 (SF-1, NR5A1) and human disease | journal = Molecular and Cellular Endocrinology | volume = 336 | issue = 1-2 | pages = 198–205 | date = April 2011 | pmid = 21078366 | pmc = 3057017 | doi = 10.1016/j.mce.2010.11.006 }}</ref> 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, [[Zygosity|homozygous]] p.R92Q change within the A-box interfered with monomeric binding stability and reduced functional activity.<ref name="Ferraz-de-Souza_2011" /> This change requires mutations to both allele to display phenotypic effects as heterozygous carriers showed normal adrenal function. | ||
[[Missense mutation|Missense]], in-frame and [[frameshift mutation]]s of NR5A1 have been found in families with 46,XY disorders of sex development, 46,XX [[gonadal dysgenesis]] and 46,XX [[premature ovarian failure|primary ovarian insufficiency]]. 46,XY individuals may have ambiguous or female genitals. Individuals of either [[karyotype]] may not enter puberty, although expression of the [[phenotype]], [[penetrance]], fertility, and modes of inheritance can vary. Some mutations are [[dominance (genetics)|dominant]], some are [[ | [[Missense mutation|Missense]], in-frame and [[frameshift mutation]]s of NR5A1 have been found in families with 46,XY disorders of sex development, 46,XX [[gonadal dysgenesis]] and 46,XX [[premature ovarian failure|primary ovarian insufficiency]]. 46,XY individuals may have ambiguous or female genitals. Individuals of either [[karyotype]] may not enter puberty, although expression of the [[phenotype]], [[penetrance]], fertility, and modes of inheritance can vary. Some mutations are [[dominance (genetics)|dominant]], some are [[Dominance (genetics)#Recessive trait|recessive]].<ref name="Lourenço_2009">{{cite journal | vauthors = Lourenço D, Brauner R, Lin L, De Perdigo A, Weryha G, Muresan M, Boudjenah R, Guerra-Junior G, Maciel-Guerra AT, Achermann JC, McElreavey K, Bashamboo A | title = Mutations in NR5A1 associated with ovarian insufficiency | journal = The New England Journal of Medicine | volume = 360 | issue = 12 | pages = 1200–10 | date = March 2009 | pmid = 19246354 | pmc = 2778147 | doi = 10.1056/NEJMoa0806228 }}</ref> | ||
=== 46, XY disorders of sex development === | === 46, XY disorders of sex development === | ||
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{{PDB Gallery|geneid=2516}} | {{PDB Gallery|geneid=2516}} | ||
{{Transcription factors|g2}} | {{Transcription factors|g2}} | ||
[[Category:Intracellular receptors]] | [[Category:Intracellular receptors]] | ||
[[Category:Transcription factors]] | [[Category:Transcription factors]] | ||
Revision as of 10:36, 29 March 2018
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The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling activity of genes related to the reproductive glands or gonads and adrenal glands.[1] 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 steroid hydroxylases, however, further roles in endocrine function have since been discovered.[2]
Structure
The NR5A1 gene encodes a 461-amino acid protein that shares several conserved domains consistent with members of the nuclear receptor subfamily.[2] 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.[3] Following binding, trans-activation of target genes depends on recruitment of co-activators such as SRC-1, GRIP1, PNRC, 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.[4]
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 revealed sequence similarities with Drosophila fushi tarazu factor I (FTZ-F1) which regulates the fushi tarazu homeobox gene.[5] Several other FTZ-F1 homologs have been identified that implicate high level of sequence conservation 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.[5]
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.[5] SF-1 specific antibody studies confirmed expression profile of SF-1 in rats[6] and humans[7] corresponding to sites of transcript detection.
Embryonic steroidogenic tissue
Genetic sex in mammals is determined by the presence or absence of the Y chromosome at fertilization. Sexually dimorphic development of embryonic gonads into testes or ovaries is activated by the SRY gene product.[8] 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.[8] 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 and granulosa cells which precedes expression of the aromatase enzyme responsible for estrogen 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 (VMH) suggesting roles beyond steroidogenic maintenance.[5]
RT-PCR approaches have detected transcripts of mice FTZ-F1 gene in the placenta and spleen; and SF-1 transcripts in the human placenta.[9]
Post-translational Regulation
Transcription capacity of SF-1 can be influenced by post-translational modification. Specifically, phosphorylation of serine 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.[10]
Function
SF-1 is a critical regulator of reproduction, regulating the transcription of key genes involved in sexual development and reproduction, most notably StAR and P450SCC. It can form a transcriptional complex with TDF to up-regulate transcription of the Sox9 gene. Its targets include genes at every level of the hypothalamic-pituitary-gonadal axis, as well as many genes involved in gonadal and adrenal steroidogenesis.[11]
SF-1 has been identified as a transcriptional regulator for an array of different genes related to sex determination and differentiation, reproduction, and metabolism via binding to their promoters. For example, SF-1 controls expression of Amh gene in Sertoli cells, whereby the presence or absence of the gene product affects development of Müllerian structures. Increased AMH protein levels leads to regression of such structures.[2] Leydig cells express SF-1 to regulate transcription of steroidogenesis and testosterone 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.[2]
| Gene | Cell/Tissue |
|---|---|
| rP450scc | granulosa cells |
| mP450scc | Y1 adrenocortical cells |
| bOxytocin | ovary |
| mStAR | MA-10 Leydig |
Sertoli cells
The Müllerian inhibiting substance (MIS) 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 established binding complexes of SF-1 to MIS,[12] 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 glycoproteins (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.[13]
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 zing 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.[2]
Sf-1 knockout mice displayed diminished corticosterone levels while maintaining elevated ACTH 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.[14]
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.[15]
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 p.G35E change to the P-box domain.[16] 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 p.R92Q change within the A-box interfered with monomeric binding stability and reduced functional activity.[16] This change requires mutations to both allele to display phenotypic effects as heterozygous carriers showed normal adrenal function.
Missense, in-frame and frameshift mutations of NR5A1 have been found in families with 46,XY disorders of sex development, 46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency. 46,XY individuals may have ambiguous or female genitals. Individuals of either karyotype may not enter puberty, although expression of the phenotype, penetrance, fertility, and modes of inheritance can vary. Some mutations are dominant, some are recessive.[17]
46, XY disorders of sex development
Heterozygous NR5A1 changes are emerging as a frequent contributor in 46, XY complete gonadal dysgenesis.[16] In affected individuals, sexual development does not match their chromosomal makeup. Males, despite having 46, XY karyotype, develop female external genitalia (uterus and fallopian tubes) along with gonadal defects rendering them nonfunctional.[18] 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.[16]
Typically, these genetic changes are frameshift, nonsense, or 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. Furthermore, one report of homozygous missense mutation p.D293N within the ligand-binding domain of SF-1 revealed autosomal recessive inheritance was also possible.[17]
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.[19] 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:
References
- ↑ Reference, Genetics Home. "NR5A1 gene". Genetics Home Reference. Retrieved 2017-11-30.
- ↑ 2.0 2.1 2.2 2.3 2.4 Parker KL, Schimmer BP (June 1997). "Steroidogenic factor 1: a key determinant of endocrine development and function". Endocrine Reviews. 18 (3): 361–77. doi:10.1210/edrv.18.3.0301. PMID 9183568.
- ↑ Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (December 1995). "The nuclear receptor superfamily: the second decade". Cell. 83 (6): 835–9. doi:10.1016/0092-8674(95)90199-x. PMID 8521507.
- ↑ Honda S, Morohashi K, Nomura M, Takeya H, Kitajima M, Omura T (April 1993). "Ad4BP regulating steroidogenic P-450 gene is a member of steroid hormone receptor superfamily". The Journal of Biological Chemistry. 268 (10): 7494–502. PMID 8463279.
- ↑ 5.0 5.1 5.2 5.3 Ikeda Y, Lala DS, Luo X, Kim E, Moisan MP, Parker KL (July 1993). "Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression". Molecular Endocrinology. 7 (7): 852–60. doi:10.1210/mend.7.7.8413309. PMID 8413309.
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- ↑ Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA (June 1994). "Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade". Cell. 77 (5): 651–61. doi:10.1016/0092-8674(94)90050-7. PMID 8205615.
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- ↑ Reference, Genetics Home. "Swyer syndrome". Genetics Home Reference. Retrieved 2017-11-30.
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- ↑ Kennell JA, O'Leary EE, Gummow BM, Hammer GD, MacDougald OA (August 2003). "T-cell factor 4N (TCF-4N), a novel isoform of mouse TCF-4, synergizes with beta-catenin to coactivate C/EBPalpha and steroidogenic factor 1 transcription factors". Molecular and Cellular Biology. 23 (15): 5366–75. doi:10.1128/MCB.23.15.5366-5375.2003. PMC 165725. PMID 12861022.
- ↑ Mizusaki H, Kawabe K, Mukai T, Ariyoshi E, Kasahara M, Yoshioka H, Swain A, Morohashi K (April 2003). "Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1) gene transcription is regulated by wnt4 in the female developing gonad". Molecular Endocrinology. 17 (4): 507–19. doi:10.1210/me.2002-0362. PMID 12554773.
- ↑ Lopez D, Shea-Eaton W, Sanchez MD, McLean MP (December 2001). "DAX-1 represses the high-density lipoprotein receptor through interaction with positive regulators sterol regulatory element-binding protein-1a and steroidogenic factor-1". Endocrinology. 142 (12): 5097–106. doi:10.1210/endo.142.12.8523. PMID 11713202.
- ↑ Sugawara T, Saito M, Fujimoto S (August 2000). "Sp1 and SF-1 interact and cooperate in the regulation of human steroidogenic acute regulatory protein gene expression". Endocrinology. 141 (8): 2895–903. doi:10.1210/en.141.8.2895. PMID 10919277.
- ↑ Mellgren G, Børud B, Hoang T, Yri OE, Fladeby C, Lien EA, Lund J (May 2003). "Characterization of receptor-interacting protein RIP140 in the regulation of SF-1 responsive target genes". Molecular and Cellular Endocrinology. 203 (1–2): 91–103. doi:10.1016/S0303-7207(03)00097-2. PMID 12782406.
- ↑ Sugawara T, Abe S, Sakuragi N, Fujimoto Y, Nomura E, Fujieda K, Saito M, Fujimoto S (August 2001). "RIP 140 modulates transcription of the steroidogenic acute regulatory protein gene through interactions with both SF-1 and DAX-1". Endocrinology. 142 (8): 3570–7. doi:10.1210/en.142.8.3570. PMID 11459805.
- ↑ De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P (November 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 (11): 6653–65. doi:10.1128/mcb.18.11.6653. PMC 109250. PMID 9774680.
- ↑ Gizard F, Lavallee B, DeWitte F, Teissier E, Staels B, Hum DW (October 2002). "The transcriptional regulating protein of 132 kDa (TReP-132) enhances P450scc gene transcription through interaction with steroidogenic factor-1 in human adrenal cells". The Journal of Biological Chemistry. 277 (42): 39144–55. doi:10.1074/jbc.M205786200. PMID 12101186.
Further reading
- Morohashi KI, Omura T (December 1996). "Ad4BP/SF-1, a transcription factor essential for the transcription of steroidogenic cytochrome P450 genes and for the establishment of the reproductive function". FASEB Journal. 10 (14): 1569–77. PMID 9002548.
- Achermann JC, Meeks JJ, Jameson JL (December 2001). "Phenotypic spectrum of mutations in DAX-1 and SF-1". Molecular and Cellular Endocrinology. 185 (1–2): 17–25. doi:10.1016/S0303-7207(01)00619-0. PMID 11738790.
- Ozisik G, Achermann JC, Jameson JL (June 2002). "The role of SF1 in adrenal and reproductive function: insight from naturally occurring mutations in humans". Molecular Genetics and Metabolism. 76 (2): 85–91. doi:10.1016/S1096-7192(02)00032-X. PMID 12083805.
- de-Souza BF, Lin L, Achermann JC (June 2006). "Steroidogenic factor-1 (SF-1) and its relevance to pediatric endocrinology". Pediatric Endocrinology Reviews. 3 (4): 359–64. doi:10.1159/000094108. PMID 16816804.
- Sadovsky Y, Crawford PA, Woodson KG, Polish JA, Clements MA, Tourtellotte LM, Simburger K, Milbrandt J (November 1995). "Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids". Proceedings of the National Academy of Sciences of the United States of America. 92 (24): 10939–43. doi:10.1073/pnas.92.24.10939. PMC 40546. PMID 7479914.
- Sasano H, Shizawa S, Suzuki T, Takayama K, Fukaya T, Morohashi K, Nagura H (August 1995). "Ad4BP in the human adrenal cortex and its disorders". The Journal of Clinical Endocrinology and Metabolism. 80 (8): 2378–80. doi:10.1210/jc.80.8.2378. PMID 7629233.
- Oba K, Yanase T, Nomura M, Morohashi K, Takayanagi R, Nawata H (September 1996). "Structural characterization of human Ad4bp (SF-1) gene". Biochemical and Biophysical Research Communications. 226 (1): 261–7. doi:10.1006/bbrc.1996.1343. PMID 8806624.
- Asa SL, Bamberger AM, Cao B, Wong M, Parker KL, Ezzat S (June 1996). "The transcription activator steroidogenic factor-1 is preferentially expressed in the human pituitary gonadotroph". The Journal of Clinical Endocrinology and Metabolism. 81 (6): 2165–70. doi:10.1210/jc.81.6.2165. PMID 8964846.
- Bamberger AM, Ezzat S, Cao B, Wong M, Parker KL, Schulte HM, Asa SL (June 1996). "Expression of steroidogenic factor-1 (SF-1) mRNA and protein in the human placenta". Molecular Human Reproduction. 2 (6): 457–61. doi:10.1093/molehr/2.6.457. PMID 9238716.
- Crawford PA, Polish JA, Ganpule G, Sadovsky Y (October 1997). "The activation function-2 hexamer of steroidogenic factor-1 is required, but not sufficient for potentiation by SRC-1". Molecular Endocrinology. 11 (11): 1626–35. doi:10.1210/me.11.11.1626. PMID 9328345.
- Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA (May 1998). "Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression". Cell. 93 (3): 445–54. doi:10.1016/S0092-8674(00)81172-1. PMID 9590178.
- Hammer GD, Krylova I, Zhang Y, Darimont BD, Simpson K, Weigel NL, Ingraham HA (April 1999). "Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruitment: integration of hormone signaling in reproduction and stress". Molecular Cell. 3 (4): 521–6. doi:10.1016/S1097-2765(00)80480-3. PMID 10230405.
- Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL (June 1999). "A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans". Nature Genetics. 22 (2): 125–6. doi:10.1038/9629. PMID 10369247.
