Cloning and sequence analysis of the human gene encoding steroidogenic factor 1

ABSTRACT The orphan nuclear receptor steroidogenic factor 1 (SF-1) plays key roles in endocrine development and function. Initially identified as a positive regulator of the cytochrome P450 steroid hydroxylases, analyses of knockout mice deficient in SF-1 revealed that SF-1 is essential for adrenal and gonadal development, pituitary gonadotropin expression and formation of the ventromedial hypothalamic nucleus. Although more limited in scope, analyses of SF-1 in humans similarly have suggested that SF-1 is important for differentiated function in adrenocortical and gonadotrope adenomas. In the hope of extending our understanding of SF-1 function by identifying possible roles of SF-1 in clinical endocrine disorders, we isolated the FTZ-F1 gene encoding human SF-1 and mapped it to chromosome 9q33. In this report, we characterize the sequence and structural organization of the human cDNA and gene encoding SF-1, providing new insights into comparative aspects of SF-1 structure that will facilitate efforts to study the role of this transcription factor in human endocrine disorders.

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Knockout Mice Lacking Steroidogenic Factor 1 Are a Novel Genetic Model of Hypothalamic Obesity

Endocrinology ◽

10.1210/endo.143.2.8652 ◽

2002 ◽

Vol 143 (2) ◽

pp. 607-614 ◽

Cited By ~ 136

Author(s):

Gregor Majdic ◽

Morag Young ◽

Elise Gomez-Sanchez ◽

Paul Anderson ◽

Lidia S. Szczepaniak ◽

...

Keyword(s):

Genetic Model ◽

Late Onset ◽

Ventromedial Hypothalamus ◽

Hypothalamic Nucleus ◽

Weight Regulation ◽

Wild Type ◽

Hypothalamic Obesity ◽

Steroidogenic Factor 1 ◽

Ventromedial Hypothalamic Nucleus

Abstract Knockout (KO) mice lacking steroidogenic factor 1 (SF-1) exhibit a phenotype that includes adrenal and gonadal agenesis, impaired gonadotropin expression, and abnormalities of the ventromedial hypothalamic nucleus (VMH). Studies in rodents with lesions of the ventromedial hypothalamus have implicated the VMH in body weight regulation, suggesting that SF-1 KO mice may provide a genetic model of obesity. To prevent death, SF-1 KO mice were rescued with corticosteroid injections, followed by syngeneic adrenal transplants from wild-type (WT) littermates. Corticosterone and ACTH levels in WT and SF-1 KO mice were indistinguishable, documenting restoration of hypothalamic-pituitary-adrenal function. Although weights at earlier ages did not differ significantly from WT littermates, SF-1 KO mice were significantly heavier by 8 wk of age and eventually weighed almost twice as much as WT controls. Obesity in SF-1 KO mice predominantly resulted from decreased activity rather than increased food intake. Leptin was increased markedly, insulin was modestly elevated, and glucose was indistinguishable from WT mice. Although sex steroids in rodents affect weight, ovariectomy did not abolish the weight difference between WT and SF-1 KO mice. These SF-1 KO mice are a genetic model of late-onset obesity that may help elucidate the role of the VMH in weight regulation.

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The cell-specific nuclear receptor steroidogenic factor 1 plays multiple roles in reproductive function

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1995.0162 ◽

1995 ◽

Vol 350 (1333) ◽

pp. 279-283 ◽

Cited By ~ 25

Keyword(s):

Nuclear Receptor ◽

Embryonic Stem ◽

Reproductive Function ◽

Gonadal Development ◽

Orphan Nuclear Receptor ◽

Gene Encoding ◽

Steroidogenic Factor 1 ◽

Steroidogenic Cell ◽

Reproductive Axis ◽

Regulated Gene Expression

The cytochrome P450 steroid hydroxylases exhibit tissue-specific and developmentally regulated gene expression. Recent studies showed that the orphan nuclear receptor steroidogenic factor 1 (SF-1) plays a key role in their gene regulation. In mouse embryos, SF-1 expression began at the inception of adrenal and gonadal development, suggesting that SF-1 plays a key role in the steroidogenic cell differentiation. SF-1 was also expressed in the developing pituitary gland and diencephalon, which raised the possibility that it also has additional roles in endocrine development. To examine the role of SF-1 in intact mice, we disrupted the gene encoding SF-1 by homologous recombination in embryonic stem cells; this approach ultimately permitted us to generate SF-1 knockout mice in which the gene encoding SF-1 was inactivated. These studies revealed essential roles of SF-1 in endocrine development that included adrenal and gonadal development, expression of several markers of pituitary gonadotropes, and formation of the ventromedial hypothalamic (VMH) nucleus. These results indicate that SF-1 acts at multiple levels of the reproductive axis to maintain reproductive competence.

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Steroidogenic Factor 1 Regulates Expression of the Cannabinoid Receptor 1 in the Ventromedial Hypothalamic Nucleus

Molecular Endocrinology ◽

10.1210/me.2008-0127 ◽

2008 ◽

Vol 22 (8) ◽

pp. 1950-1961 ◽

Cited By ~ 24

Author(s):

Ki Woo Kim ◽

Young-Hwan Jo ◽

Liping Zhao ◽

Nancy R. Stallings ◽

Streamson C. Chua ◽

...

Keyword(s):

Energy Homeostasis ◽

Cannabinoid Receptor ◽

Hypothalamic Nucleus ◽

Cannabinoid Receptor 1 ◽

Steroidogenic Factor 1 ◽

Ventromedial Hypothalamic Nucleus ◽

Hypothalamic Slice ◽

Responsive Element ◽

And Function ◽

The Brain

Abstract 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.

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Selective Loss of Leptin Receptors in the Ventromedial Hypothalamic Nucleus Results in Increased Adiposity and a Metabolic Syndrome

Endocrinology ◽

10.1210/en.2007-1200 ◽

2008 ◽

Vol 149 (5) ◽

pp. 2138-2148 ◽

Cited By ~ 142

Author(s):

Nathan C. Bingham ◽

Kimberly K. Anderson ◽

Anne L. Reuter ◽

Nancy R. Stallings ◽

Keith L. Parker

Keyword(s):

Metabolic Syndrome ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Leptin Receptor ◽

Artificial Chromosome ◽

Hypothalamic Nucleus ◽

Steroidogenic Factor 1 ◽

Low Fat Diet ◽

Ventromedial Hypothalamic Nucleus

Leptin, an adipocyte-derived hormone, has emerged as a critical regulator of energy homeostasis. The leptin receptor (Lepr) is expressed in discrete regions of the brain; among the sites of highest expression are several mediobasal hypothalamic nuclei known to play a role in energy homeostasis, including the arcuate nucleus, the ventromedial hypothalamic nucleus (VMH), and the dorsomedial hypothalamic nucleus. Although most studies have focused on leptin’s actions in the arcuate nucleus, the role of Lepr in these other sites has received less attention. To explore the role of leptin signaling in the VMH, we used bacterial artificial chromosome transgenesis to target Cre recombinase to VMH neurons expressing steroidogenic factor 1, thereby inactivating a conditional Lepr allele specifically in steroidogenic factor 1 neurons of the VMH. These knockout (KO) mice, designated Lepr KOVMH, exhibited obesity, particularly when challenged with a high-fat diet. On a low-fat diet, Lepr KOVMH mice exhibited significantly increased adipose mass even when their weights were comparable to wild-type littermates. Furthermore, these mice exhibited a metabolic syndrome including hepatic steatosis, dyslipidemia, and hyperleptinemia. Lepr KOVMH mice were hyperinsulinemic from the age of weaning and eventually developed overt glucose intolerance. These data define nonredundant roles of the Lepr in VMH neurons in energy homeostasis and provide a model system for studying other actions of leptin in the VMH.

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Evidence of Adrenal Failure in Aging Dax1-Deficient Mice

Endocrinology ◽

10.1210/en.2010-0986 ◽

2011 ◽

Vol 152 (9) ◽

pp. 3430-3439 ◽

Cited By ~ 36

Author(s):

Joshua O. Scheys ◽

Joanne H. Heaton ◽

Gary D. Hammer

Keyword(s):

Embryonic Stem ◽

Orphan Nuclear Receptor ◽

Adrenal Failure ◽

Steroidogenic Factor 1 ◽

Human Data ◽

Stem Cell Pluripotency ◽

Adrenocortical Failure ◽

And Function ◽

Embryonic Stem Cell Pluripotency

Dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1 (Dax1) is an orphan nuclear receptor essential for development and function of the mammalian adrenal cortex and gonads. DAX1 was cloned as the gene responsible for X-linked AHC, which is characterized by adrenocortical failure necessitating glucocorticoid replacement. Contrary to these human data, young mice with genetic Dax1 knockout (Dax1−/Y) exhibit adrenocortical hyperfunction, consistent with the historic description of Dax1 as a transcriptional repressor that inhibits steroidogenic factor 1-dependent steroidogenesis. This paradox of molecular function and two apparently opposite phenotypes associated with Dax1 deficiency in mice and humans is compounded by the recent observations that under certain circumstances, Dax1 can serve as a transcriptional activator of steroidogenic factor 1. The recently revealed role of Dax1 in embryonic stem cell pluripotency, together with the observation that its expression in the adult adrenal is restricted to the subcapsular cortex, where presumptive undifferentiated progenitor cells reside, has led us to reexamine the phenotype of Dax1−/Y mice in order to reconcile the conflicting mouse and human data. In this report, we demonstrate that although young Dax1−/Y mice have enhanced steroidogenesis and subcapsular adrenocortical proliferation, as these mice age, they exhibit declining adrenal growth, decreasing adrenal steroidogenic capacity, and a reversal of their initial enhanced hormonal sensitivity. Together with a marked adrenal dysplasia in aging mice, these data reveal that both Dax1−/Y mice and patients with X-linked AHC exhibit adrenal failure that is consistent with adrenocortical subcapsular progenitor cell depletion and argue for a significant role of Dax1 in maintenance of these cells.

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Two-Step Regulation of Ad4BP/SF-1 Gene Transcription during Fetal Adrenal Development: Initiation by a Hox-Pbx1-Prep1 Complex and Maintenance via Autoregulation by Ad4BP/SF-1

Molecular and Cellular Biology ◽

10.1128/mcb.00222-06 ◽

2006 ◽

Vol 26 (11) ◽

pp. 4111-4121 ◽

Cited By ~ 80

Author(s):

Mohamad Zubair ◽

Satoru Ishihara ◽

Sanae Oka ◽

Katsuzumi Okumura ◽

Ken-ichirou Morohashi

Keyword(s):

Adrenal Cortex ◽

Binding Sites ◽

Orphan Nuclear Receptor ◽

Specific Expression ◽

Steroidogenic Factor 1 ◽

Tissue Specific ◽

Adrenal Cells ◽

Tissue Specific Expression ◽

And Function ◽

Intron 4

ABSTRACT The orphan nuclear receptor Ad4BP/SF-1 (adrenal 4 binding protein/steroidogenic factor 1) is essential for the proper development and function of reproductive and steroidogenic tissues. Although the expression of Ad4BP/SF-1 is specific for those tissues, the mechanisms underlying this tissue-specific expression remain unknown. In this study, we used transgenic mouse assays to examine the regulation of the tissue-specific expression of Ad4BP/SF-1. An investigation of the entire Ad4BP/SF-1 gene locus revealed a fetal adrenal enhancer (FAdE) in intron 4 containing highly conserved binding sites for Pbx-Prep, Pbx-Hox, and Ad4BP/SF-1. Transgenic assays revealed that the Ad4 sites, together with Ad4BP/SF-1, develop an autoregulatory loop and thereby maintain transcription, while the Pbx/Prep and Pbx/Hox sites initiate transcription prior to the establishment of the autoregulatory loop. Indeed, a limited number of Hox family members were found to be expressed in the adrenal primordia. Whether a true fetal-type adrenal cortex is present in mice remained controversial, and this argument was complicated by the postnatal development of the so-called X zone. Using transgenic mice with lacZ driven by the FAdE, we clearly identified a fetal adrenal cortex in mice, and the X zone is the fetal adrenal cells accumulated at the juxtamedullary region after birth.

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Norepinephrine control of ventromedial hypothalamic nucleus glucoregulatory neurotransmitter expression in the female rat: Role of monocarboxylate transporter function

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2019.01.004 ◽

2019 ◽

Vol 95 ◽

pp. 51-58 ◽

Cited By ~ 9

Author(s):

A.S.M. Hasan Mahmood ◽

Santosh K. Mandal ◽

Khaggeswar Bheemanapally ◽

Mostafa M.H. Ibrahim ◽

K.P. Briski

Keyword(s):

Monocarboxylate Transporter ◽

Hypothalamic Nucleus ◽

Female Rat ◽

Ventromedial Hypothalamic Nucleus

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In Vivo Ablation of the Conserved GATA-Binding Motif in the Amh Promoter Impairs Amh Expression in the Male Mouse

Endocrinology ◽

10.1210/en.2019-00047 ◽

2019 ◽

Vol 160 (4) ◽

pp. 817-826 ◽

Cited By ~ 6

Author(s):

Marie France Bouchard ◽

Francis Bergeron ◽

Jasmine Grenier Delaney ◽

Louis-Mathieu Harvey ◽

Robert S Viger

Keyword(s):

Developmental Time ◽

Gonadal Development ◽

Conclusive Evidence ◽

Binding Motif ◽

Male Embryo ◽

Steroidogenic Factor 1 ◽

Protein Levels ◽

Positive Modulator ◽

And Function

Abstract GATA4 is an essential transcriptional regulator required for gonadal development, differentiation, and function. In the developing testis, proposed GATA4-regulated genes include steroidogenic factor 1 (Nr5a1), SRY-related HMG box 9 (Sox9), and anti-Müllerian hormone (Amh). Although some of these genes have been validated as genuine GATA4 targets, it remains unclear whether GATA4 is a direct regulator of endogenous Amh transcription. We used a CRISPR/Cas9-based approach to specifically inactivate or delete the sole GATA-binding motif of the proximal mouse Amh promoter. AMH mRNA and protein levels were assessed at developmental time points corresponding to elevated AMH levels: fetal and neonate testes in males and adult ovaries in females. In males, loss of GATA binding to the Amh promoter significantly reduced Amh expression. Although the loss of GATA binding did not block the initiation of Amh transcription, AMH mRNA and protein levels failed to upregulate in the developing fetal and neonate testis. Interestingly, adult male mice presented no anatomical anomalies and had no evidence of retained Müllerian duct structures, suggesting that AMH levels, although markedly reduced, were sufficient to masculinize the male embryo. In contrast to males, GATA binding to the Amh promoter was dispensable for Amh expression in the adult ovary. These results provide conclusive evidence that in males, GATA4 is a positive modulator of Amh expression that works in concert with other key transcription factors to ensure that the Amh gene is sufficiently expressed in a correct spatiotemporal manner during fetal and prepubertal testis development.

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