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SF-1 a key player in the development and differentiation of steroidogenic tissues.

Val P, Lefrançois-Martinez AM, Veyssière G, Martinez A - Nucl. Recept. (2003)

Bottom Line: SF-1 is also an essential regulator of genes involved in the sex determination cascade.In particular, the role of SF-1 in the hormonal responsiveness of steroidogenic genes promoters is still a subject of debate.It also summarizes the pros and cons regarding the presumed role of SF-1 in cAMP signalling.

View Article: PubMed Central - HTML - PubMed

Affiliation: UMR CNRS 6547, Physiologie Comparée et Endocrinologie Moléculaire, Université Blaise Pascal, Clermont II, Complexe Universitaire des Cézeaux, 24 avenue des Landais, 63177 Aubiere Cedex, France. a-marie.lefrancois-martinez@univ-bpclermont.fr

ABSTRACT
Since its discovery in the early 1990s, the orphan nuclear receptor SF-1 has been attributed a central role in the development and differentiation of steroidogenic tissues. SF-1 controls the expression of all the steroidogenic enzymes and cholesterol transporters required for steroidogenesis as well as the expression of steroidogenesis-stimulating hormones and their cognate receptors. SF-1 is also an essential regulator of genes involved in the sex determination cascade. The study of SF-1 mice and of human mutants has been of great value to demonstrate the essential role of this factor in vivo, although the complete adrenal and gonadal agenesis in knock-out animals has impeded studies of its function as a transcriptional regulator. In particular, the role of SF-1 in the hormonal responsiveness of steroidogenic genes promoters is still a subject of debate. This extensive review takes into account recent data obtained from SF-1 haploinsufficient mice, pituitary-specific knock-outs and from transgenic mice experiments carried out with SF-1 target gene promoters. It also summarizes the pros and cons regarding the presumed role of SF-1 in cAMP signalling.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of SF-1 regulatory regions. A summary of the experimental results obtained with SF-1 regulatory regions in humans, rats and mice is presented. Cis elements are conserved across the three species. Numbering may vary from one species to another. Pod-1/Capsulin and USF bind to the same response element. USF activates SF-1 transcription whereas Pod-1 is likely to repress it. Abreviations : GATA, GATA proteins response element; Sox BS, Sox proteins binding site; CAT, CAAT box; Sp1, Sp1 response element; Inr, initiator; SFRE, SF-1 responsive element; USF, upstream stimulatory factor; CBF, CAT box binding factor.
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Figure 4: Schematic representation of SF-1 regulatory regions. A summary of the experimental results obtained with SF-1 regulatory regions in humans, rats and mice is presented. Cis elements are conserved across the three species. Numbering may vary from one species to another. Pod-1/Capsulin and USF bind to the same response element. USF activates SF-1 transcription whereas Pod-1 is likely to repress it. Abreviations : GATA, GATA proteins response element; Sox BS, Sox proteins binding site; CAT, CAAT box; Sp1, Sp1 response element; Inr, initiator; SFRE, SF-1 responsive element; USF, upstream stimulatory factor; CBF, CAT box binding factor.

Mentions: A small 90 bp SF-1 proximal promoter is specifically expressed in adrenocortical cells in transient transfections. This region encompasses an E-box (-87/-82), a Sp1 binding site (-30/-24) and a CAT box that binds CBF (-68/-59) [120,121] (figure 4). If the role of the latter is not clearly demonstrated, transcriptional control of SF-1 expression at least requires the E-box which is conserved in human and which is functional in both steroidogenic and non-steroidogenic cells [120,122-124]. This element is able to bind the ubiquitous USF factor contained within pituitary αT3-1 cells, steroidogenic Y1 and JEG-3 cells, as well as CV1 and HeLa cells [123]. None of these interactions however, can account for tissue-restricted SF-1 expression. SF-1 itself is able to bind a site which is present in its own first intron in rat and human genes (+156/+163) [124,125] (figure 4). Whereas Nomura et al., [125] have shown the role of this sequence for the expression of a reporter gene in Y1 cells, or in response to SF-1 overexpression in heterologous CV-1 cells, Woodson et al., using the rat gene and Oba et al., using the human gene, were unable to obtain the same results in either steroidogenic or non-steroidogenic cells [120,124]. However, it is worth considering that some sequences contained within the first intron might be required for SF-1 expression, though their specificity is not yet established [124]. This is confirmed by the use of different lengths of SF-1 regulatory regions and intragenic sequences in transgenic mice [49,126]. SF-1 is expressed in the urogenital ridge as early as E9.5 at similar levels in males and females. When sex determination occurs between E10.5 and E12.5, SF-1 expression strongly decreases in the ovary until E18.5, whereas it remains elevated in the testis. After birth, expression rises in the ovary although it is reduced in adult testis [26,27]. Pod-1/Capsulin is a transcription factor of the b-HLH family which is able to heterodimerize with other factors of the family by binding to E-boxes (figure 4). It participates to kidney and lung differentiation [127] and displays a sexually dimorphic pattern of expression in the gonad, which is reminescent of SF-1 gonadal expression. However, Pod-1 is expressed in gonadal regions where SF-1 is not expressed (i.e. coelomic epithelial cells, peritubular myoid cells and epithelial-like cells). In fact, it seems that Pod-1 may act as a repressor of SF-1 promoter activity through interaction with the previously described E-box [128]. Sox9 and SF-1 are colocalized in somatic cells of the testis and follow parallel expression patterns during development [129]. They both participate to transcriptional activation of the MIS promoter in males [105]. Recent results show that Sox9 is able to induce SF-1 expression in heterologous cells and that a Sox9 binding site (-110/-104) is required for SF-1 expression in Sertoli and Y1 cells [130] (figure 4). GATA-4 is also dimorphically expressed in the gonad. Whereas its expression is high in the undetermined gonad it decreases as ovary differentiation starts, although it is maintained in the testis. This dimorphism may participate to the control of MIS expression [131], but GATA-4 is also able to moderately activate SF-1 expression via a conserved site at -177/-172 (figure 4). This activation is dependent on the cell type and seems to be essentially restricted to Sertoli cells where SF-1 participates to MIS expression [132]. Although most elements required for SF-1 expression in steroidogenic tissues are likely to be localized in the 5' flanking regions and first intron of the gene, a GFP/SF-1 fusion, the expression of which is directed by a 50 kb BAC comprised of SF-1 promoter, first exon and first intron, is not expressed in pituitary gonadotropes [49]. Although a single transgenic line was studied so far, this indicates that further downstream sequences might be required for pituitary expression. However, there is no mention of pituitary expression in the work of Zubair et al., who used SF-1 regulatory regions extending from the first intron to the seventh exon [126]. Altogether, these data allow a better understanding of SF-1 tissue-specific expression especially in the gonads but do not establish a link between SF-1 transcription and the cAMP signalling pathway.


SF-1 a key player in the development and differentiation of steroidogenic tissues.

Val P, Lefrançois-Martinez AM, Veyssière G, Martinez A - Nucl. Recept. (2003)

Schematic representation of SF-1 regulatory regions. A summary of the experimental results obtained with SF-1 regulatory regions in humans, rats and mice is presented. Cis elements are conserved across the three species. Numbering may vary from one species to another. Pod-1/Capsulin and USF bind to the same response element. USF activates SF-1 transcription whereas Pod-1 is likely to repress it. Abreviations : GATA, GATA proteins response element; Sox BS, Sox proteins binding site; CAT, CAAT box; Sp1, Sp1 response element; Inr, initiator; SFRE, SF-1 responsive element; USF, upstream stimulatory factor; CBF, CAT box binding factor.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC240021&req=5

Figure 4: Schematic representation of SF-1 regulatory regions. A summary of the experimental results obtained with SF-1 regulatory regions in humans, rats and mice is presented. Cis elements are conserved across the three species. Numbering may vary from one species to another. Pod-1/Capsulin and USF bind to the same response element. USF activates SF-1 transcription whereas Pod-1 is likely to repress it. Abreviations : GATA, GATA proteins response element; Sox BS, Sox proteins binding site; CAT, CAAT box; Sp1, Sp1 response element; Inr, initiator; SFRE, SF-1 responsive element; USF, upstream stimulatory factor; CBF, CAT box binding factor.
Mentions: A small 90 bp SF-1 proximal promoter is specifically expressed in adrenocortical cells in transient transfections. This region encompasses an E-box (-87/-82), a Sp1 binding site (-30/-24) and a CAT box that binds CBF (-68/-59) [120,121] (figure 4). If the role of the latter is not clearly demonstrated, transcriptional control of SF-1 expression at least requires the E-box which is conserved in human and which is functional in both steroidogenic and non-steroidogenic cells [120,122-124]. This element is able to bind the ubiquitous USF factor contained within pituitary αT3-1 cells, steroidogenic Y1 and JEG-3 cells, as well as CV1 and HeLa cells [123]. None of these interactions however, can account for tissue-restricted SF-1 expression. SF-1 itself is able to bind a site which is present in its own first intron in rat and human genes (+156/+163) [124,125] (figure 4). Whereas Nomura et al., [125] have shown the role of this sequence for the expression of a reporter gene in Y1 cells, or in response to SF-1 overexpression in heterologous CV-1 cells, Woodson et al., using the rat gene and Oba et al., using the human gene, were unable to obtain the same results in either steroidogenic or non-steroidogenic cells [120,124]. However, it is worth considering that some sequences contained within the first intron might be required for SF-1 expression, though their specificity is not yet established [124]. This is confirmed by the use of different lengths of SF-1 regulatory regions and intragenic sequences in transgenic mice [49,126]. SF-1 is expressed in the urogenital ridge as early as E9.5 at similar levels in males and females. When sex determination occurs between E10.5 and E12.5, SF-1 expression strongly decreases in the ovary until E18.5, whereas it remains elevated in the testis. After birth, expression rises in the ovary although it is reduced in adult testis [26,27]. Pod-1/Capsulin is a transcription factor of the b-HLH family which is able to heterodimerize with other factors of the family by binding to E-boxes (figure 4). It participates to kidney and lung differentiation [127] and displays a sexually dimorphic pattern of expression in the gonad, which is reminescent of SF-1 gonadal expression. However, Pod-1 is expressed in gonadal regions where SF-1 is not expressed (i.e. coelomic epithelial cells, peritubular myoid cells and epithelial-like cells). In fact, it seems that Pod-1 may act as a repressor of SF-1 promoter activity through interaction with the previously described E-box [128]. Sox9 and SF-1 are colocalized in somatic cells of the testis and follow parallel expression patterns during development [129]. They both participate to transcriptional activation of the MIS promoter in males [105]. Recent results show that Sox9 is able to induce SF-1 expression in heterologous cells and that a Sox9 binding site (-110/-104) is required for SF-1 expression in Sertoli and Y1 cells [130] (figure 4). GATA-4 is also dimorphically expressed in the gonad. Whereas its expression is high in the undetermined gonad it decreases as ovary differentiation starts, although it is maintained in the testis. This dimorphism may participate to the control of MIS expression [131], but GATA-4 is also able to moderately activate SF-1 expression via a conserved site at -177/-172 (figure 4). This activation is dependent on the cell type and seems to be essentially restricted to Sertoli cells where SF-1 participates to MIS expression [132]. Although most elements required for SF-1 expression in steroidogenic tissues are likely to be localized in the 5' flanking regions and first intron of the gene, a GFP/SF-1 fusion, the expression of which is directed by a 50 kb BAC comprised of SF-1 promoter, first exon and first intron, is not expressed in pituitary gonadotropes [49]. Although a single transgenic line was studied so far, this indicates that further downstream sequences might be required for pituitary expression. However, there is no mention of pituitary expression in the work of Zubair et al., who used SF-1 regulatory regions extending from the first intron to the seventh exon [126]. Altogether, these data allow a better understanding of SF-1 tissue-specific expression especially in the gonads but do not establish a link between SF-1 transcription and the cAMP signalling pathway.

Bottom Line: SF-1 is also an essential regulator of genes involved in the sex determination cascade.In particular, the role of SF-1 in the hormonal responsiveness of steroidogenic genes promoters is still a subject of debate.It also summarizes the pros and cons regarding the presumed role of SF-1 in cAMP signalling.

View Article: PubMed Central - HTML - PubMed

Affiliation: UMR CNRS 6547, Physiologie Comparée et Endocrinologie Moléculaire, Université Blaise Pascal, Clermont II, Complexe Universitaire des Cézeaux, 24 avenue des Landais, 63177 Aubiere Cedex, France. a-marie.lefrancois-martinez@univ-bpclermont.fr

ABSTRACT
Since its discovery in the early 1990s, the orphan nuclear receptor SF-1 has been attributed a central role in the development and differentiation of steroidogenic tissues. SF-1 controls the expression of all the steroidogenic enzymes and cholesterol transporters required for steroidogenesis as well as the expression of steroidogenesis-stimulating hormones and their cognate receptors. SF-1 is also an essential regulator of genes involved in the sex determination cascade. The study of SF-1 mice and of human mutants has been of great value to demonstrate the essential role of this factor in vivo, although the complete adrenal and gonadal agenesis in knock-out animals has impeded studies of its function as a transcriptional regulator. In particular, the role of SF-1 in the hormonal responsiveness of steroidogenic genes promoters is still a subject of debate. This extensive review takes into account recent data obtained from SF-1 haploinsufficient mice, pituitary-specific knock-outs and from transgenic mice experiments carried out with SF-1 target gene promoters. It also summarizes the pros and cons regarding the presumed role of SF-1 in cAMP signalling.

No MeSH data available.


Related in: MedlinePlus