The Experts below are selected from a list of 3855 Experts worldwide ranked by ideXlab platform
K L Parker - One of the best experts on this subject based on the ideXlab platform.
-
Hypomorphic phenotype in mice with pituitary-specific knockout of Steroidogenic Factor 1.
Genesis, 2020Co-Authors: L Zhao, Marit Bakke, Yelena Krimkevich, Lisa J. Cushman, Albert F. Parlow, Sally A. Camper, K L ParkerAbstract:Summary: The bacteriophage Cre recombinase provides a powerful approach for tissue-specific gene inactivation. Using a Cre transgene driven by the common alpha subunit of glycoprotein hormones (αGSU-Cre), we have previously inactivated Steroidogenic Factor 1 (SF-1) in the anterior pituitary, causing hypogonadotropic hypogonadism with sexual infantilism, sterility, and severe gonadal hypoplasia. We now explore the molecular mechanisms underlying a hypomorphic gonadal phenotype in mice carrying two floxed SF-1 alleles (F/F) relative to mice carrying one recombined and one floxed allele (F/R). Because their Cre-mediated disruption of the locus encoding SF-1 was less efficient, αGSU-Cre, F/F mice retained some gonadotropin-expressing cells in the anterior pituitary, thereby stimulating some gonadal function. This novel in vivo model for exploring the effects of differing levels of gonadotropins on gonadal development highlights the need for careful genotype-phenotype comparisons in studies using Cre recombinase to produce tissue-specific knockouts. genesis 30:65–69, 2001. © 2001 Wiley-Liss, Inc.
-
Steroidogenic Factor 1 directs programs regulating diet induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: L Zhao, K L Parker, Jose Donato, Daisuke Kohno, Yong Xu, Carol F Elias, Joel K ElmquistAbstract:The transcription Factor Steroidogenic Factor 1 (SF-1) is exclusively expressed in the brain in the ventral medial hypothalamic nucleus (VMH) and is required for the development of this nucleus. However, the physiological importance of transcriptional programs regulated by SF-1 in the VMH is not well defined. To delineate the functional significance of SF-1 itself in the brain, we generated pre- and postnatal VMH-specific SF-1 KO mice. Both models of VMH-specific SF-1 KO were susceptible to high fat diet-induced obesity and displayed impaired thermogenesis after acute exposure to high fat diet. Furthermore, VMH-specific SF-1 KO mice showed significantly decreased LepR expression specifically in the VMH, leading to leptin resistance. Collectively, these results indicate that SF-1 directs transcriptional programs in the hypothalamus relevant to coordinated control of energy homeostasis, especially after excess caloric intake.
-
Central nervous system-specific knockout of Steroidogenic Factor 1.
Molecular and cellular endocrinology, 2008Co-Authors: L Zhao, K L ParkerAbstract:Steroidogenic Factor 1 (SF-1) is a nuclear receptor that plays important roles in the hypothalamus-pituitary-Steroidogenic organ axis. Global knockout studies in mice revealed the essential in vivo roles of SF-1 in the ventromedial hypothalamic (VMH) nucleus, adrenal glands, and gonads. One limitation of global SF-1 knockout mice is their early postnatal death from adrenocortical insufficiency. To overcome limitations of the global knockout mice and to delineate the roles of SF-1 in the brain, we used Cre/loxP recombination technology to genetically ablate SF-1 specifically in the central nervous system (CNS). Mice with CNS-specific knockout of SF-1 mediated by nestin-Cre showed increased anxiety-like behavior, revealing a crucial role of SF-1 in a complex behavioral phenotype. Our studies with CNS-specific SF-1 KO mice also defined roles of SF-1 in regulating the VMH expression of target genes implicated in anxiety and energy homeostasis. Therefore, this review will focus on our recent studies defining the functional roles of SF-1 in the VMH linked to anxiety and energy homeostasis.
-
Steroidogenic Factor 1 regulates expression of the cannabinoid receptor 1 in the ventromedial hypothalamic nucleus.
Molecular Endocrinology, 2008Co-Authors: Young-hwan Jo, L Zhao, Nancy R Stallings, Streamson C. Chua, K L ParkerAbstract:The nuclear receptor Steroidogenic Factor 1 (SF-1) plays essential roles in the development and function of the ventromedial hypothalamic nucleus (VMH). Considerable evidence links the VMH and SF-1 with the regulation of energy homeostasis. Here, we demonstrate that SF-1 colocalizes in VMH neurons with the cannabinoid receptor 1 (CB1R) and that a specific CB1R agonist modulates electrical activity of SF-1 neurons in hypothalamic slice preparations. We further show that SF-1 directly regulates CB1R gene expression via a SF-1-responsive element at −101 in its 5′-flanking region. Finally, we show that knockout mice with selective inactivation of SF-1 in the brain have decreased expression of CB1R in the region of the VMH and exhibit a blunted response to systemically administered CB1R agonists. These studies suggest that SF-1 directly regulates the expression of CB1R, which has been implicated in the regulation of energy homeostasis and anxiety-like behavior.
-
development of a Steroidogenic Factor 1 cre transgenic mouse line
Genesis, 2006Co-Authors: Nathan C Bingham, Sunita Vermakurvari, Luis F Parada, K L ParkerAbstract:The Cre-loxP strategy provides an approach to disrupt genes in specific tissues and/or cell types, circumventing lethality associated with global knockouts or secondary effects due to gene inactivation at other sites. A critical component is the development of transgenes that target Cre expression to specific cell types. Here, we describe the use of bacterial artificial chromosome (BAC) transgenesis to target Cre expression to tissues that express Steroidogenic Factor 1 (SF-1, officially designated Nr5a1). Consistent with the SF-1 expression pattern, the SF-1 BAC directed Cre expression to the somatic cells of the gonads, the adrenal cortex, the anterior pituitary, the spleen, and the ventromedial hypothalamic nucleus. This transgene provides a powerful tool to inactivate genes of interest in these tissues. genesis 44:419–424, 2006. Published 2006 Wiley-Liss, Inc.
Holly A Ingraham - One of the best experts on this subject based on the ideXlab platform.
-
differential requirement for Steroidogenic Factor 1 gene dosage in adrenal development versus endocrine function
Molecular Endocrinology, 2004Co-Authors: Michelle L Bland, Robert C Fowkes, Holly A IngrahamAbstract:The importance of Steroidogenic Factor-1 (SF-1) gene dosage in endocrine function is evidenced by phenotypes associated with the heterozygous state in mice and humans. Here we examined mechanisms underlying SF-1 haploinsufficiency and found a striking reduction (12-fold) in SF-1 heterozygous (+/−) adrenocortical size at embryonic day (E) 12. Loss of one SF-1 allele led to a selective decrease in adrenal precursors within the adrenogonadal primordium at E10.0, without affecting the number of gonadal precursors, as marked by GATA-4. Beginning at E13.5, increased cell proliferation in SF-1 +/− adrenals allows these organs to approach but not attain a normal size. Remarkably, neural crest-derived adrenomedullary precursors migrated normally in SF-1 +/− and null embryos. However, later in development, medullary growth was compromised in both genotypes. Despite the small adrenal size in SF-1heterozygotes, an unexpected elevation in Steroidogenic capacity per cell was observed in primary adult adrenocortical SF-...
-
wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing Steroidogenic Factor 1 β catenin synergy
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Brian K Jordan, Jennifer Shen, Holly A Ingraham, Robert Olaso, Eric VilainAbstract:Genetic studies in mice suggest that Wnt4 signaling antagonizes expression of male hormones and effectively blocks male development in the female embryo. We recently identified an XY intersex patient carrying a chromosomal duplication of the WNT4 locus and proposed that this patient's feminization arises from an increased dosage of WNT4. To test this hypothesis, a transgenic mouse was generated with a large genomic P1 containing the human WNT4. Although a complete male to female intersex phenotype was not observed in WNT4 transgenic male mice, a dramatic reduction in Steroidogenic acute regulatory protein was detected consistent with the marked reduction in serum and testicular androgen levels. Furthermore, a mild reduction of germ cells and a disorganized vascular system were observed in testes of WNT4 transgenic males. Consistent with these in vivo data, Wnt4 repressed steroidogenesis in adrenocortical and Leydig cell lines, as evidenced by reduced progesterone secretion and 3β-hydroxysteroid dehydrogenase activity. In vitro studies showed that Wnt4 antagonizes the functional synergy observed between the major effector of the Wnt signaling pathway, β-catenin and Steroidogenic Factor 1, and chromatin immunoprecipitation showed that Wnt4 attenuates recruitment of β-catenin to the Steroidogenic acute regulatory protein promoter. Our findings suggest a model in which Wnt4 acts as an anti-male Factor by disrupting recruitment of β-catenin at or near Steroidogenic Factor 1 binding sites present in multiple Steroidogenic genes.
-
Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing Steroidogenic Factor 1/β-catenin synergy
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Brian K Jordan, Jennifer Shen, Holly A Ingraham, Robert Olaso, Eric VilainAbstract:Genetic studies in mice suggest that Wnt4 signaling antagonizes expression of male hormones and effectively blocks male development in the female embryo. We recently identified an XY intersex patient carrying a chromosomal duplication of the WNT4 locus and proposed that this patient's feminization arises from an increased dosage of WNT4. To test this hypothesis, a transgenic mouse was generated with a large genomic P1 containing the human WNT4. Although a complete male to female intersex phenotype was not observed in WNT4 transgenic male mice, a dramatic reduction in Steroidogenic acute regulatory protein was detected consistent with the marked reduction in serum and testicular androgen levels. Furthermore, a mild reduction of germ cells and a disorganized vascular system were observed in testes of WNT4 transgenic males. Consistent with these in vivo data, Wnt4 repressed steroidogenesis in adrenocortical and Leydig cell lines, as evidenced by reduced progesterone secretion and 3β-hydroxysteroid dehydrogenase activity. In vitro studies showed that Wnt4 antagonizes the functional synergy observed between the major effector of the Wnt signaling pathway, β-catenin and Steroidogenic Factor 1, and chromatin immunoprecipitation showed that Wnt4 attenuates recruitment of β-catenin to the Steroidogenic acute regulatory protein promoter. Our findings suggest a model in which Wnt4 acts as an anti-male Factor by disrupting recruitment of β-catenin at or near Steroidogenic Factor 1 binding sites present in multiple Steroidogenic genes.
-
regulation of the orphan nuclear receptor Steroidogenic Factor 1 by sox proteins
Molecular Endocrinology, 2002Co-Authors: Jennifer Shen, Holly A IngrahamAbstract:Steroidogenic Factor 1 (SF-1) is an essential Factor in endocrine proliferation and gene expression. Despite the fact that SF-1 expression is restricted to specialized cells within the endocrine system, the only identified regulatory Factors of SF-1 are the ubiquitously expressed E-box proteins (upstream stimulatory Factors 1 and 2). Sequence examination of the SF-1 proximal promoter revealed a conserved site of AACAAAG (Sox-BS1), which matches exactly the defined consensus Sox protein binding element. Among the approximately 20 known members of the Sox gene family, we focused on Sox3, Sox8, and Sox9, based on their coexpression with SF-1 in the embryonic testis. Indeed, all three of these Sox proteins were capable of binding the proximal Sox-BS1 within the SF-1 promoter (−110 to −104), albeit with differing affinities. Of the three Sox proteins, Sox9 exhibited high-affinity binding to the Sox-BS1 element and consistently activated SF-1 promoter-reporter constructs. Mutating the Sox-BS1 attenuated SF-1 pr...
-
haploinsufficiency of Steroidogenic Factor 1 in mice disrupts adrenal development leading to an impaired stress response
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Michelle L Bland, Christina Jamieson, Susan F Akana, Stefan R Bornstein, Graeme Eisenhofer, Mary F Dallman, Holly A IngrahamAbstract:Adrenal steroids are essential for homeostasis and survival during severe physiological stress. Analysis of a patient heterozygous for the Steroidogenic Factor-1 (SF-1) gene suggested that reduced expression of this nuclear receptor leads to adrenal failure. We therefore examined SF-1 heterozygous (+/−) mice as a potential model for delineating mechanisms underlying this disease. Here we show that SF-1 +/− mice exhibit adrenal insufficiency resulting from profound defects in adrenal development and organization. However, compensatory mechanisms, such as cellular hypertrophy and increased expression of the rate-limiting Steroidogenic protein StAR, help to maintain adrenal function at near normal capacity under basal conditions. In contrast, adrenal deficits in SF-1 heterozygotes are revealed under stressful conditions, demonstrating that normal gene dosage of SF-1 is required for mounting an adequate stress response. Our findings predict that natural variations leading to reduced SF-1 function may underlie some forms of subclinical adrenal insufficiency, which become life threatening during traumatic stress.
L Zhao - One of the best experts on this subject based on the ideXlab platform.
-
Hypomorphic phenotype in mice with pituitary-specific knockout of Steroidogenic Factor 1.
Genesis, 2020Co-Authors: L Zhao, Marit Bakke, Yelena Krimkevich, Lisa J. Cushman, Albert F. Parlow, Sally A. Camper, K L ParkerAbstract:Summary: The bacteriophage Cre recombinase provides a powerful approach for tissue-specific gene inactivation. Using a Cre transgene driven by the common alpha subunit of glycoprotein hormones (αGSU-Cre), we have previously inactivated Steroidogenic Factor 1 (SF-1) in the anterior pituitary, causing hypogonadotropic hypogonadism with sexual infantilism, sterility, and severe gonadal hypoplasia. We now explore the molecular mechanisms underlying a hypomorphic gonadal phenotype in mice carrying two floxed SF-1 alleles (F/F) relative to mice carrying one recombined and one floxed allele (F/R). Because their Cre-mediated disruption of the locus encoding SF-1 was less efficient, αGSU-Cre, F/F mice retained some gonadotropin-expressing cells in the anterior pituitary, thereby stimulating some gonadal function. This novel in vivo model for exploring the effects of differing levels of gonadotropins on gonadal development highlights the need for careful genotype-phenotype comparisons in studies using Cre recombinase to produce tissue-specific knockouts. genesis 30:65–69, 2001. © 2001 Wiley-Liss, Inc.
-
Steroidogenic Factor 1 directs programs regulating diet induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: L Zhao, K L Parker, Jose Donato, Daisuke Kohno, Yong Xu, Carol F Elias, Joel K ElmquistAbstract:The transcription Factor Steroidogenic Factor 1 (SF-1) is exclusively expressed in the brain in the ventral medial hypothalamic nucleus (VMH) and is required for the development of this nucleus. However, the physiological importance of transcriptional programs regulated by SF-1 in the VMH is not well defined. To delineate the functional significance of SF-1 itself in the brain, we generated pre- and postnatal VMH-specific SF-1 KO mice. Both models of VMH-specific SF-1 KO were susceptible to high fat diet-induced obesity and displayed impaired thermogenesis after acute exposure to high fat diet. Furthermore, VMH-specific SF-1 KO mice showed significantly decreased LepR expression specifically in the VMH, leading to leptin resistance. Collectively, these results indicate that SF-1 directs transcriptional programs in the hypothalamus relevant to coordinated control of energy homeostasis, especially after excess caloric intake.
-
Central nervous system-specific knockout of Steroidogenic Factor 1.
Molecular and cellular endocrinology, 2008Co-Authors: L Zhao, K L ParkerAbstract:Steroidogenic Factor 1 (SF-1) is a nuclear receptor that plays important roles in the hypothalamus-pituitary-Steroidogenic organ axis. Global knockout studies in mice revealed the essential in vivo roles of SF-1 in the ventromedial hypothalamic (VMH) nucleus, adrenal glands, and gonads. One limitation of global SF-1 knockout mice is their early postnatal death from adrenocortical insufficiency. To overcome limitations of the global knockout mice and to delineate the roles of SF-1 in the brain, we used Cre/loxP recombination technology to genetically ablate SF-1 specifically in the central nervous system (CNS). Mice with CNS-specific knockout of SF-1 mediated by nestin-Cre showed increased anxiety-like behavior, revealing a crucial role of SF-1 in a complex behavioral phenotype. Our studies with CNS-specific SF-1 KO mice also defined roles of SF-1 in regulating the VMH expression of target genes implicated in anxiety and energy homeostasis. Therefore, this review will focus on our recent studies defining the functional roles of SF-1 in the VMH linked to anxiety and energy homeostasis.
-
Steroidogenic Factor 1 regulates expression of the cannabinoid receptor 1 in the ventromedial hypothalamic nucleus.
Molecular Endocrinology, 2008Co-Authors: Young-hwan Jo, L Zhao, Nancy R Stallings, Streamson C. Chua, K L ParkerAbstract:The nuclear receptor Steroidogenic Factor 1 (SF-1) plays essential roles in the development and function of the ventromedial hypothalamic nucleus (VMH). Considerable evidence links the VMH and SF-1 with the regulation of energy homeostasis. Here, we demonstrate that SF-1 colocalizes in VMH neurons with the cannabinoid receptor 1 (CB1R) and that a specific CB1R agonist modulates electrical activity of SF-1 neurons in hypothalamic slice preparations. We further show that SF-1 directly regulates CB1R gene expression via a SF-1-responsive element at −101 in its 5′-flanking region. Finally, we show that knockout mice with selective inactivation of SF-1 in the brain have decreased expression of CB1R in the region of the VMH and exhibit a blunted response to systemically administered CB1R agonists. These studies suggest that SF-1 directly regulates the expression of CB1R, which has been implicated in the regulation of energy homeostasis and anxiety-like behavior.
-
cell specific knockout of Steroidogenic Factor 1 reveals its essential roles in gonadal function
Molecular Endocrinology, 2004Co-Authors: Pancharatnam Jeyasuria, L Zhao, Yayoi Ikeda, Soazik P Jamin, Dirk G De Rooij, Axel P N Themmen, Richard R Behringer, K L ParkerAbstract:Knockout (KO) mice lacking the orphan nuclear receptor Steroidogenic Factor 1 (SF-1, officially designated Nr5a1) have a compound endocrine phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and structural abnormalities of the ventromedial hypothalamic nucleus. To inactivate a conditional SF-1 allele in the gonads, we targeted the expression of Cre recombinase with a knock-in allele of the anti-Mullerian hormone type 2 receptor locus. In testes, Cre was expressed in Leydig cells. The testes of adult gonad-specific SF-1 KO mice remained at the level of the bladder and were markedly hypoplastic, due at least partly to impaired spermatogenesis. Histological abnormalities of the testes were seen from early developmental stages and were associated with markedly decreased Leydig cell expression of two essential components of testosterone biosynthesis, Cyp11a and the Steroidogenic acute regulatory protein. In females, the anti-Mullerian hormone type 2 receptor-C...
Marit Bakke - One of the best experts on this subject based on the ideXlab platform.
-
Hypomorphic phenotype in mice with pituitary-specific knockout of Steroidogenic Factor 1.
Genesis, 2020Co-Authors: L Zhao, Marit Bakke, Yelena Krimkevich, Lisa J. Cushman, Albert F. Parlow, Sally A. Camper, K L ParkerAbstract:Summary: The bacteriophage Cre recombinase provides a powerful approach for tissue-specific gene inactivation. Using a Cre transgene driven by the common alpha subunit of glycoprotein hormones (αGSU-Cre), we have previously inactivated Steroidogenic Factor 1 (SF-1) in the anterior pituitary, causing hypogonadotropic hypogonadism with sexual infantilism, sterility, and severe gonadal hypoplasia. We now explore the molecular mechanisms underlying a hypomorphic gonadal phenotype in mice carrying two floxed SF-1 alleles (F/F) relative to mice carrying one recombined and one floxed allele (F/R). Because their Cre-mediated disruption of the locus encoding SF-1 was less efficient, αGSU-Cre, F/F mice retained some gonadotropin-expressing cells in the anterior pituitary, thereby stimulating some gonadal function. This novel in vivo model for exploring the effects of differing levels of gonadotropins on gonadal development highlights the need for careful genotype-phenotype comparisons in studies using Cre recombinase to produce tissue-specific knockouts. genesis 30:65–69, 2001. © 2001 Wiley-Liss, Inc.
-
Epigenetic regulation of the gene encoding Steroidogenic Factor-1
Molecular and Cellular Endocrinology, 2013Co-Authors: Erling A Hoivik, Trine Elholm Bjånesøy, Marit BakkeAbstract:The nuclear receptor Steroidogenic Factor 1 (SF-1) is expressed in a precise time and cell-specific pattern in the endocrine system. Three intronic enhancers and one upstream enhancer, which are required for controlling the restricted expression of SF-1, have been identified in the mouse gene encoding SF-1. In recent years, efforts from several laboratories have established that expression of SF-1 is controlled by DNA methylation. CpG-sites are found in the basal promoter as well as in the intronic enhancers, and the methylation status of these genomic regions nearly perfectly correlates with their transcriptional activity such that they are hypomethylated in tissues where they are active, and generally hypermethylated in tissues where they are not active. This review summarizes the present knowledge of how tissue differentially methylated regions control the transcriptional activity of the SF-1 gene, and how irregularities in the methylation pattern can contribute to disease development.
-
molecular aspects of Steroidogenic Factor 1 sf 1
Molecular and Cellular Endocrinology, 2010Co-Authors: Erling A Hoivik, Aurelia E Lewis, Linda Aumo, Marit BakkeAbstract:Abstract Steroidogenic Factor 1 (SF-1, also called Ad4BP and NR5A1) is a nuclear receptor with critical roles in Steroidogenic tissues, as well as in the brain and pituitary. In particular, SF-1 has emerged as an essential regulator of adrenal and gonadal functions and development. In the last few years, our knowledge on SF-1 has increased considerably at all levels, from the gene to the protein, and on its specific roles in different physiological processes. In this review, we discuss the current understanding on SF-1 with focus on the parameters that control the transcriptional capacity of SF-1 and the mechanisms that ensure proper stage- and tissue-specific expression of the gene encoding SF-1.
-
Deoxyribonucleic Acid Methylation Controls Cell Type-Specific Expression of Steroidogenic Factor 1
Endocrinology, 2008Co-Authors: Erling A Hoivik, Aurelia E Lewis, Linda Aumo, Neil A Hanley, Nancy R Stallings, Reidun Aesoy, Haldis Lillefosse, Rebecca M. Perrett, Marit BakkeAbstract:Steroidogenic Factor 1 (SF1) is expressed in a time- and cell-specific manner in the endocrine system. In this study we present evidence to support that methylation of CpG sites located in the proximal promoter of the gene encoding SF1 contributes to the restricted expression pattern of this nuclear receptor. DNA methylation analyses revealed a nearly perfect correlation between the methylation status of the proximal promoter and protein expression, such that it was hypomethylated in cells that express SF1 but hypermethylated in nonexpressing cells. Moreover, in vitro methylation of this region completely repressed reporter gene activity in transfected Steroidogenic cells. Bisulfite sequencing of DNA from embryonic tissue demonstrated that the proximal promoter was unmethylated in the developing testis and ovary, whereas it was hypermethylated in tissues that do not express SF1. Together these results indicate that the DNA methylation pattern is established early in the embryo and stably inherited thereaf...
-
Phosphorylation of Steroidogenic Factor 1 Is Mediated by Cyclin-Dependent Kinase 7
Molecular Endocrinology, 2007Co-Authors: Aurelia E Lewis, Erling A Hoivik, Marte Rusten, Elisabeth L. Vikse, Magnus Hansson, Annika E. Wallberg, Marit BakkeAbstract:The nuclear receptor Steroidogenic Factor-1 (SF1) is critical for development and function of Steroidogenic tissues. Posttranslational modifications are known to influence the transcriptional capacity of SF1, and it was previously demonstrated that serine 203 is phosphorylated. In this paper we report that serine 203 is phosphorylated by a cyclin-dependent kinase 7 (CDK7)-mediated process. As part of the CDK-activating kinase complex, CDK7 is a component of the basal transcription Factor TFIIH, and phosphorylation of SF1 as well as SF1-dependent transcription was clearly reduced in cells carrying a mutation that renders the CDK-activating kinase complex unable to interact with the TFIIH core. Coimmunoprecipitation analyses revealed that SF1 and CDK7 reside in the same complex, and kinase assays demonstrated that immunoprecipitated CDK7 and purified TFIIH phosphorylate SF1 in vitro. The CDK inhibitor roscovitine blocked phosphorylation of SF1, and an inactive form of CDK7 repressed the phosphorylation leve...
John C Achermann - One of the best experts on this subject based on the ideXlab platform.
-
Steroidogenic Factor 1 and human disease
Seminars in Reproductive Medicine, 2012Co-Authors: Ranna Elkhairi, John C AchermannAbstract:Steroidogenic Factor-1 (SF-1) (Ad4BP, NR5A1) is a nuclear receptor that plays a key role in adrenal and reproductive development and function. Deletion of the gene encoding Sf-1 (Nr5a1) in mice results in severe developmental defects of the adrenal gland and gonad. Consequently, initial work on the potential effects of SF-1 disruption in humans focused on individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis, and Mullerian structures. This is a rare phenotype, but has been reported on two occasions, because of alterations that affect key DNA-binding domains of SF-1. Attention then turned to a potential wider role of SF-1 in human adrenal and reproductive disorders. Although changes in SF-1 only very rarely cause isolated adrenal failure, it is emerging that variations in SF-1 are a surprisingly frequent cause of reproductive dysfunction in humans. In 46,XY disorders of sex development, a spectrum of phenotypes has been reported including severe and partial forms of gonadal (testicular) dysgenesis, hypospadias, anorchia with microphallus, and even male Factor infertility. In 46,XX females, alterations in SF-1 are associated with primary ovarian insufficiency. Thus, SF-1 seems be a more significant Factor in human reproductive health than was first envisioned, with implications for adults as well as children.
-
Steroidogenic Factor 1 sf 1 nr5a1 and human disease
Molecular and Cellular Endocrinology, 2011Co-Authors: Bruno Ferrazdesouza, John C AchermannAbstract:Steroidogenic Factor-1 (SF-1, Ad4BP, encoded by NR5A1) is a key regulator of adrenal and reproductive development and function. Based upon the features found in Nr5a1 null mice, initial attempts to identify SF-1 changes in humans focused on those rare individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis and Mullerian structures. Although alterations affecting DNA-binding of SF-1 were found in two such cases, disruption of SF-1 is not commonly found in patients with adrenal failure. In contrast, it is emerging that variations in SF-1 can be found in association with a range of human reproductive phenotypes such as 46,XY disorders of sex development (DSD), hypospadias, anorchia, male Factor infertility, or primary ovarian insufficiency in women. Overexpression or overactivity of SF-1 is also reported in some adrenal tumors or endometriosis. Therefore, the clinical spectrum of phenotypes associated with variations in SF-1 is expanding and the importance of this nuclear receptor in human endocrine disease is now firmly established.
-
sterol o acyltransferase 1 soat1 acat is a novel target of Steroidogenic Factor 1 sf 1 nr5a1 ad4bp in the human adrenal
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Bruno Ferrazdesouza, R E Hudsondavies, Rahul Parnaik, Mike Hubank, Mehul T Dattani, John C AchermannAbstract:We used up- and down-regulation of the nuclear receptor Steroidogenic Factor-1 (SF-1, NR5A1, Ad4BP) to identify new components of adrenal function and steroidogenesis.
-
update Steroidogenic Factor 1 sf 1 nr5a1
Minerva Endocrinologica, 2010Co-Authors: Birgit Kohler, John C AchermannAbstract:Steroidogenic Factor 1 (SF1, NR5A1, Ad4BP) is a nuclear receptor and regulator of multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Complete deletion of Nr5a1 in XY mice results in adrenal and gonadal agenesis, female external genitalia and presence of Mullerian structures. These findings were first reported in the early 1990s. Subsequently, NR5A1 mutations were found in two 46,XY phenotypic females with Mullerian structures and adrenal failure and in one 46,XX female with adrenal failure. More recently, heterozygous NR5A1 mutations have been identified in a substantial proportion of patients with 46,XY disorders of sex development (46,XY DSD) without adrenal insufficiency. Most of these individuals display severe underandrogenization with ambiguous genitalia at birth, partial gonadal dysgenesis, and absence of Mullerian structures or remnants. Some of the patients have a milder phenotype such as hypospadias and cryptorchidism, due to less severe defects in androgen synthesis. Testosterone, inhibin B and AMH are usually low indicating a partial (or sometimes progressive) form of gonadal dysgenesis in most cases. However, normal testosterone production at birth might also be present. The frequency of NR5A1 mutations in otherwise unexplained 46,XY DSD with underandrogenization and partial testicular dysgenesis has been estimated to be about 15%. Furthermore, NR5A1 mutations have now been found in women with familial and sporadic 46,XX primary ovarian insufficiency without adrenal failure. These human phenotypes associated with NR5A1 mutations show that SF-1 is a key Factor involved in both human testis and ovarian development, but that human adrenal development seems to be more resistant to the effects of SF-1 haploinsufficiency than gonadal development. Patients with 46,XY DSD and mild underandrogenization due to partial testicular dysgenesis should possibly be assigned to the male sex, as small testes with Leydig, Sertoli and germ cells are present in almost all cases. Additionally, spontaneous virilization in puberty might be possible in patients with NR5A1 mutations. However, fertility options and the risk of testicular malignancy and adrenal insufficiency in adulthood are unknown and need to be investigated in long-term outcome studies.
-
the spectrum of phenotypes associated with mutations in Steroidogenic Factor 1 sf 1 nr5a1 ad4bp includes severe penoscrotal hypospadias in 46 xy males without adrenal insufficiency
European Journal of Endocrinology, 2009Co-Authors: Birgit Kohler, Inas Mazen, Cigdem Cetindag, Heike Biebermann, Ilker Akkurt, Rainer Rossi, Olaf Hiort, Annette Gruters, John C AchermannAbstract:Objective Hypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic Factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias.
