Steroidogenic factor 1The 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. It was originally identified as a regulator of genes encoding cytochrome P steroid hydroxylaseshowever, further roles in endocrine function have steroidogenic factor 1 genecard been discovered. The NR5A1 gene encodes a amino acid protein that shares several conserved domains consistent with members of dbol gym nuclear receptor steroidogenicc. Other critical domains of SF-1 include a proline-rich hinge region, ligand-binding domain, and clean step C-terminal activation domain for transcriptional interactions. The hinge region steroidogenic factor 1 genecard undergo post-transcriptional and translational modifications such as phosphorylation by cAMP-dependent kinasethat further enhance stability and transcriptional activity.
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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. It was originally identified as a regulator of genes encoding cytochrome P steroid hydroxylases , however, further roles in endocrine function have since been discovered.
The NR5A1 gene encodes a amino acid protein that shares several conserved domains consistent with members of the nuclear receptor subfamily. Other critical domains of SF-1 include a proline-rich hinge region, ligand-binding domain, and a C-terminal activation domain for transcriptional interactions.
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. For example, SF-1 cDNA shares an identical base-pair sequence with embryonal long terminal repeat-binding protein ELP cDNA isolated from embryonal carcinoma cells , differing only in their terminal ends.
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. 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. 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: 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.
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. Transcription capacity of SF-1 can be influenced by post-translational modification. Specifically, phosphorylation of serine is mediated by cyclin-dependent kinase 7.
This inactivity has shown to repress phosphorylation of SF-1 and SFdependent transcription. SF-1 is a critical regulator of reproduction, regulating the transcription of key genes involved in sexual development and reproduction, most notably StAR and P SCC. 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.
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. Increased AMH protein levels leads to regression of such structures. 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.
Gel mobility shift experiments and use of SFspecific polyclonal antibodies established binding complexes of SF-1 to MIS,  however, other studies suggest the MIS promoter is repressed and not activated by SF-1 binding. Studies have implicated SF-1 as an upstream regulator of a collection of genes required for gonadotrope function via GSE.
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. Several approaches used targeted gene disruption in mouse embryonic stem cells with the aim of identifying potential target genes of SF The corresponding observed phenotypic effects on endocrine development and function were found to be quite similar.
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. 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. Mutations in NR5A1 can produce intersex genitals, absence of puberty, and infertility. 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. G35E change may have a mild competitive or dominant negative effect on transactivation resulting in severe gonadal defects and adrenal dysfunction. R92Q change within the A-box interfered with monomeric binding stability and reduced functional activity.
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. 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. Heterozygous NR5A1 changes are emerging as a frequent contributor in 46, XY complete gonadal dysgenesis.
Males, despite having 46, XY karyotype , develop female external genitalia uterus and fallopian tubes along with gonadal defects rendering them nonfunctional. 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. DN within the ligand-binding domain of SF-1 revealed autosomal recessive inheritance was also possible. 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.
It is important to note further studies are required to establish the relationship between SF-1 changes and infertility. From Wikipedia, the free encyclopedia. Chromosome 9 human . The Journal of Biological Chemistry. The Journal of Clinical Endocrinology and Metabolism. The Embryo Project Encyclopedia".
The tale of steroidogenic factor-1". Molecular and Cellular Endocrinology. The New England Journal of Medicine. American Journal of Human Genetics. Molecular and Cellular Biology. Molecular Genetics and Metabolism.
Biochemical and Biophysical Research Communications. Structure of the steroidogenic factor-1 ligand binding domain bound to phospholipid and a SHP peptide motif. Transcription factors and intracellular receptors. A B C Octamer transcription factor: Retrieved from " https: Genes on human chromosome 9 Intracellular receptors Transcription factors.
More reference expression data.