The Experts below are selected from a list of 50580 Experts worldwide ranked by ideXlab platform
K L Parker - One of the best experts on this subject based on the ideXlab platform.
-
0888-8809/02/$15.00/0 Molecular Endocrinology 16(10):2360–2370 Printed in U.S.A. Copyright © 2002 by The Endocrine Society doi: 10.1210/me.2002-0003 Development of a Transgenic Green Fluorescent Protein Lineage Marker for Steroidogenic Factor 1
2013Co-Authors: Nancy R Stallings, Marit Bakke, Gregor Majdic, Neil A Hanley, Liping Zhao, K L ParkerAbstract:Knockout mice lacking steroidogenic factor 1 (SF-1, officially designated Nr5a1) have a complex phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and structural abnormalities of the ventromedial hypothalamic nucleus. To explore further how SF-1 regulates Endocrine function, we used bacterial artificial chromosome transgenesis to develop a lineage marker for SF-1-expressing cells. A genomic fragment containing 50 kb of the mouse Nr5a1 gene was used to target enhanced green fluorescent protein (eGFP) in transgenic mice. These sequences directed eGFP to multiple cell lineages that express SF-1, including steroidogenic cells of the adrenal cortex, testes, and ovaries, neurons of the ventromedial hypothalamic nucleus, and reticuloendothelial cells of the spleen. Despite the proven role of SF-1 in gonadotrope function, eGFP was not expressed in the anterior pituitary. These experiments show that 50 kb of the mouse Nr5a1 gene can target transgenic expression to multiple cell lineages that normally express SF-1. The SF-1/eGFP transgenic mice will facilitate approaches such as fluorescence-activated cell sorting of eGFP-positive cells and DNA microarray analyses to expand our understanding of the multiple actions of SF-1 in Endocrine Development an
-
a novel mutation in the accessory dna binding domain of human steroidogenic factor 1 causes xy gonadal dysgenesis without adrenal insufficiency
European Journal of Endocrinology, 2007Co-Authors: Anne L Reuter, Nathan C Bingham, Katsumi Goji, Masafumi Matsuo, K L ParkerAbstract:Objective: Steroidogenic factor 1 (SF1), officially designated NR5A1, is a nuclear receptor that plays key roles in Endocrine Development and function. Previous reports of human SF1 mutations revealed a spectrum of phenotypes affecting adrenal function and/or gonadal Development and sex differentiation. We present the clinical phenotype and functional effects of a novel SF1 mutation. Patient: The patient is a 22-year-old 46, XY Japanese patient who presented with dysgenetic testes, atrophic vasa deferentia and epididymides, lack of Mullerian structures, and clitoromegaly. Endocrine studies revealed normal adrenal function. Results: Analysis of the SF1 gene revealed compound heterozygosity for a previously described p.G146A polymorphism and a novel missense mutation (p.R84C) in the accessory DNA-binding domain. The father carried the p.G146A polymorphism and the mother had the p.R84C mutation; both were clinically and reproductively normal. Functional studies demonstrated that the p.R84C SF1 had normal nuclear localization but decreased DNA-binding affinity and transcriptional activity compared with wild-type SF1; it did not exhibit any dominant negative activity. Conclusions: These results describe the human phenotype that results from compound heterozygosity of the p.G146A polymorphism and a novel p.R84C mutation of SF1, thereby extending the spectrum of human SF1 mutations that impair testis Development and sex differentiation in a sex-limited manner while preserving normal adrenal function.
-
a microdeletion in the ligand binding domain of human steroidogenic factor 1 causes xy sex reversal without adrenal insufficiency
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Rafaela V Correa, K L Parker, Nathan C Bingham, Sorahia Domenice, Ana Elisa C Billerbeck, William E Rainey, Berenice B MendoncaAbstract:Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that plays key roles in Endocrine Development and function. Knockout mice lacking SF-1 have adrenal and gonadal agenesis, impaired gonadotropin expression, and structural abnormalities of the ventromedial hypothalamic nucleus. Previous studies have identified three human subjects with mutations in SF-1 causing adrenocortical insufficiency with varying degrees of gonadal dysfunction. We now describe a novel 8-bp microdeletion of SF-1, isolated from a 46, XY patient who presented with gonadal agenesis but normal adrenal function, which causes premature termination upstream of sequences encoding the activation function 2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wild-type protein in most cell types. To our knowledge, this is the first example of an apparent dominant-negative effect of a SF-1 mutation in humans. These findings, which define a ...
-
A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency.
The Journal of clinical endocrinology and metabolism, 2004Co-Authors: Rafaela V Correa, K L Parker, Nathan C Bingham, Sorahia Domenice, Ana Elisa C Billerbeck, William E Rainey, Berenice B MendoncaAbstract:Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that plays key roles in Endocrine Development and function. Knockout mice lacking SF-1 have adrenal and gonadal agenesis, impaired gonadotropin expression, and structural abnormalities of the ventromedial hypothalamic nucleus. Previous studies have identified three human subjects with mutations in SF-1 causing adrenocortical insufficiency with varying degrees of gonadal dysfunction. We now describe a novel 8-bp microdeletion of SF-1, isolated from a 46, XY patient who presented with gonadal agenesis but normal adrenal function, which causes premature termination upstream of sequences encoding the activation function 2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wild-type protein in most cell types. To our knowledge, this is the first example of an apparent dominant-negative effect of a SF-1 mutation in humans. These findings, which define a SF-1 mutation that apparently differentially affects its transcriptional activity in vivo in the adrenal cortex and the gonads, may be relevant to the cohort of patients who present with 46, XY sex reversal but normal adrenal function.
-
steroidogenic factor 1 an essential mediator of Endocrine Development
Recent Progress in Hormone Research, 2002Co-Authors: K L Parker, Marit Bakke, Claudia Frigeri, Douglas A Rice, Margaret Wong, Deepak S. Lala, Neil A Hanley, Yayoi Ikeda, Nancy R StallingsAbstract:The orphan nuclear receptor steroidogenic factor 1 (SF-1, also called Ad4BP and officially designated NR5A1) has emerged as an essential regulator of Endocrine Development and function. Initially identified as a tissue-specific transcriptional regulator of the cytochrome P450 steroid hydroxylases, SF-1 has considerably broader roles, as evidenced from studies in knockout mice lacking SF-1. The SF-1-knockout mice lacked adrenal glands and gonads and therefore died from adrenal insufficiency within the first week after birth. In addition, SF-1 knockout mice exhibited male-to-female sex reversal of their internal and external genitalia, impaired expression of multiple markers of pituitary gonadotropes, and agenesis of the ventromedial hypothalamic nucleus (VMH). These studies delineated essential roles of SF-1 in regulating Endocrine differentiation and function at multiple levels, particularly with respect to reproduction. This chapter will review the experiments that established SF-1 as a pivotal, global determinant of Endocrine differentiation and function. We next discuss recent insights into the mechanisms controlling the expression and function of SF-1 as well as the current status of research aimed at delineating its roles in specific tissues. Finally, we highlight areas where additional studies are needed to expand our understanding of SF-1 action.
Nathan C Bingham - One of the best experts on this subject based on the ideXlab platform.
-
a novel mutation in the accessory dna binding domain of human steroidogenic factor 1 causes xy gonadal dysgenesis without adrenal insufficiency
European Journal of Endocrinology, 2007Co-Authors: Anne L Reuter, Nathan C Bingham, Katsumi Goji, Masafumi Matsuo, K L ParkerAbstract:Objective: Steroidogenic factor 1 (SF1), officially designated NR5A1, is a nuclear receptor that plays key roles in Endocrine Development and function. Previous reports of human SF1 mutations revealed a spectrum of phenotypes affecting adrenal function and/or gonadal Development and sex differentiation. We present the clinical phenotype and functional effects of a novel SF1 mutation. Patient: The patient is a 22-year-old 46, XY Japanese patient who presented with dysgenetic testes, atrophic vasa deferentia and epididymides, lack of Mullerian structures, and clitoromegaly. Endocrine studies revealed normal adrenal function. Results: Analysis of the SF1 gene revealed compound heterozygosity for a previously described p.G146A polymorphism and a novel missense mutation (p.R84C) in the accessory DNA-binding domain. The father carried the p.G146A polymorphism and the mother had the p.R84C mutation; both were clinically and reproductively normal. Functional studies demonstrated that the p.R84C SF1 had normal nuclear localization but decreased DNA-binding affinity and transcriptional activity compared with wild-type SF1; it did not exhibit any dominant negative activity. Conclusions: These results describe the human phenotype that results from compound heterozygosity of the p.G146A polymorphism and a novel p.R84C mutation of SF1, thereby extending the spectrum of human SF1 mutations that impair testis Development and sex differentiation in a sex-limited manner while preserving normal adrenal function.
-
crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor 1
Molecular Cell, 2005Co-Authors: Yong Li, Mihwa Choi, Greg Cavey, Jennifer Daugherty, Kelly Suino, Amanda Kovach, Nathan C Bingham, Steven A Kliewer, Eric H XuAbstract:Abstract The orphan nuclear receptor steroidogenic factor 1 (SF-1) regulates the differentiation and function of Endocrine glands. Although SF-1 is constitutively active in cell-based assays, it is not known whether this transcriptional activity is modulated by ligands. Here, we describe the 1.5 A crystal structure of the SF-1 ligand binding domain in complex with an LXXLL motif from a coregulator protein. The structure reveals the presence of a phospholipid ligand in a surprisingly large pocket (∼1600 A 3 ), with the receptor adopting the canonical active conformation. The bound phospholipid is readily exchanged and modulates SF-1 interactions with coactivators. Mutations designed to reduce the size of the SF-1 pocket or to disrupt hydrogen bonds with the phospholipid abolish SF-1/coactivator interactions and significantly reduce SF-1 transcriptional activity. These findings provide evidence that SF-1 is regulated by endogenous ligands and suggest an unexpected relationship between phospholipids and Endocrine Development and function.
-
Crystallographic Identification and Functional Characterization of Phospholipids as Ligands for the Orphan Nuclear Receptor Steroidogenic Factor-1
Molecular Cell, 2005Co-Authors: Mihwa Choi, Greg Cavey, Jennifer Daugherty, Kelly Suino, Amanda Kovach, Nathan C Bingham, Steven A KliewerAbstract:The orphan nuclear receptor steroidogenic factor 1 (SF-1) regulates the differentiation and function of Endocrine glands. Although SF-1 is constitutively active in cell-based assays, it is not known whether this transcriptional activity is modulated by ligands. Here, we describe the 1.5 angstroms crystal structure of the SF-1 ligand binding domain in complex with an LXXLL motif from a coregulator protein. The structure reveals the presence of a phospholipid ligand in a surprisingly large pocket (approximately 1600 angstroms3), with the receptor adopting the canonical active conformation. The bound phospholipid is readily exchanged and modulates SF-1 interactions with coactivators. Mutations designed to reduce the size of the SF-1 pocket or to disrupt hydrogen bonds with the phospholipid abolish SF-1/coactivator interactions and significantly reduce SF-1 transcriptional activity. These findings provide evidence that SF-1 is regulated by endogenous ligands and suggest an unexpected relationship between phospholipids and Endocrine Development and function.
-
a microdeletion in the ligand binding domain of human steroidogenic factor 1 causes xy sex reversal without adrenal insufficiency
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Rafaela V Correa, K L Parker, Nathan C Bingham, Sorahia Domenice, Ana Elisa C Billerbeck, William E Rainey, Berenice B MendoncaAbstract:Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that plays key roles in Endocrine Development and function. Knockout mice lacking SF-1 have adrenal and gonadal agenesis, impaired gonadotropin expression, and structural abnormalities of the ventromedial hypothalamic nucleus. Previous studies have identified three human subjects with mutations in SF-1 causing adrenocortical insufficiency with varying degrees of gonadal dysfunction. We now describe a novel 8-bp microdeletion of SF-1, isolated from a 46, XY patient who presented with gonadal agenesis but normal adrenal function, which causes premature termination upstream of sequences encoding the activation function 2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wild-type protein in most cell types. To our knowledge, this is the first example of an apparent dominant-negative effect of a SF-1 mutation in humans. These findings, which define a ...
-
A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency.
The Journal of clinical endocrinology and metabolism, 2004Co-Authors: Rafaela V Correa, K L Parker, Nathan C Bingham, Sorahia Domenice, Ana Elisa C Billerbeck, William E Rainey, Berenice B MendoncaAbstract:Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that plays key roles in Endocrine Development and function. Knockout mice lacking SF-1 have adrenal and gonadal agenesis, impaired gonadotropin expression, and structural abnormalities of the ventromedial hypothalamic nucleus. Previous studies have identified three human subjects with mutations in SF-1 causing adrenocortical insufficiency with varying degrees of gonadal dysfunction. We now describe a novel 8-bp microdeletion of SF-1, isolated from a 46, XY patient who presented with gonadal agenesis but normal adrenal function, which causes premature termination upstream of sequences encoding the activation function 2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wild-type protein in most cell types. To our knowledge, this is the first example of an apparent dominant-negative effect of a SF-1 mutation in humans. These findings, which define a SF-1 mutation that apparently differentially affects its transcriptional activity in vivo in the adrenal cortex and the gonads, may be relevant to the cohort of patients who present with 46, XY sex reversal but normal adrenal function.
Giovanna Camerino - One of the best experts on this subject based on the ideXlab platform.
-
steroidogenic factor 1 and dax 1 colocalize in multiple cell lineages potential links in Endocrine Development
Molecular Endocrinology, 1996Co-Authors: Yoi Ikeda, Amanda Swain, Katherine Tamai, Robin Lovellbadge, Elena Zanaria, Kathryn E Hentges, Enzo Lalli, Paolo Sassonecorsi, Thomas Weber, Giovanna CamerinoAbstract:Mutations of the orphan nuclear receptors, steroidogenic factor 1 (SF-1) and DAX-1, cause complex Endocrine phenotypes that include impaired adrenal Development and hypogonadotrophic hypogonadism. These similar phenotypes suggest that SF-1 and DAX-1 act in the same pathway(s) of Endocrine Development. To explore this model, we now compare directly their sites of expression. In mouse embryos, SF-1 expression in the urogenital ridge and brain either preceded or coincided with Dax-1 expression, with coordinate expression thereafter in the adrenal cortex, testis, ovary, hypothalamus, and anterior pituitary. The striking colocalization of SF-1 and Dax-1 supports the model that they are intimately linked in a common pathway of Endocrine Development. The slightly earlier onset of SF-1 expression and its ability to bind specifically to a conserved sequence in the Dax-1 5'-flanking region suggested that SF-1 may activate Dax-1 expression. However, promoter activity of Dax-1 5'-flanking sequences did not require th...
-
Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in Endocrine Development.
Molecular Endocrinology, 1996Co-Authors: Yoi Ikeda, Amanda Swain, Katherine Tamai, Elena Zanaria, Kathryn E Hentges, Enzo Lalli, Thomas Weber, Paolo Sassone-corsi, Robin Lovell-badge, Giovanna CamerinoAbstract:Mutations of the orphan nuclear receptors, steroidogenic factor 1 (SF-1) and DAX-1, cause complex Endocrine phenotypes that include impaired adrenal Development and hypogonadotrophic hypogonadism. These similar phenotypes suggest that SF-1 and DAX-1 act in the same pathway(s) of Endocrine Development. To explore this model, we now compare directly their sites of expression. In mouse embryos, SF-1 expression in the urogenital ridge and brain either preceded or coincided with Dax-1 expression, with coordinate expression thereafter in the adrenal cortex, testis, ovary, hypothalamus, and anterior pituitary. The striking colocalization of SF-1 and Dax-1 supports the model that they are intimately linked in a common pathway of Endocrine Development. The slightly earlier onset of SF-1 expression and its ability to bind specifically to a conserved sequence in the Dax-1 5'-flanking region suggested that SF-1 may activate Dax-1 expression. However, promoter activity of Dax-1 5'-flanking sequences did not require this potential SF-1-responsive element, and Dax-1 expression was unimpaired in knockout mice lacking SF-1, establishing that SF-1 is not required for Dax-1 gene expression in these settings. Although the precise mechanisms remain to be established and may be multifactorial, our results strongly suggest that these two orphan nuclear receptors interact in a common pathway of Endocrine Development.
Berenice B Mendonca - One of the best experts on this subject based on the ideXlab platform.
-
a microdeletion in the ligand binding domain of human steroidogenic factor 1 causes xy sex reversal without adrenal insufficiency
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Rafaela V Correa, K L Parker, Nathan C Bingham, Sorahia Domenice, Ana Elisa C Billerbeck, William E Rainey, Berenice B MendoncaAbstract:Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that plays key roles in Endocrine Development and function. Knockout mice lacking SF-1 have adrenal and gonadal agenesis, impaired gonadotropin expression, and structural abnormalities of the ventromedial hypothalamic nucleus. Previous studies have identified three human subjects with mutations in SF-1 causing adrenocortical insufficiency with varying degrees of gonadal dysfunction. We now describe a novel 8-bp microdeletion of SF-1, isolated from a 46, XY patient who presented with gonadal agenesis but normal adrenal function, which causes premature termination upstream of sequences encoding the activation function 2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wild-type protein in most cell types. To our knowledge, this is the first example of an apparent dominant-negative effect of a SF-1 mutation in humans. These findings, which define a ...
-
A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency.
The Journal of clinical endocrinology and metabolism, 2004Co-Authors: Rafaela V Correa, K L Parker, Nathan C Bingham, Sorahia Domenice, Ana Elisa C Billerbeck, William E Rainey, Berenice B MendoncaAbstract:Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that plays key roles in Endocrine Development and function. Knockout mice lacking SF-1 have adrenal and gonadal agenesis, impaired gonadotropin expression, and structural abnormalities of the ventromedial hypothalamic nucleus. Previous studies have identified three human subjects with mutations in SF-1 causing adrenocortical insufficiency with varying degrees of gonadal dysfunction. We now describe a novel 8-bp microdeletion of SF-1, isolated from a 46, XY patient who presented with gonadal agenesis but normal adrenal function, which causes premature termination upstream of sequences encoding the activation function 2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wild-type protein in most cell types. To our knowledge, this is the first example of an apparent dominant-negative effect of a SF-1 mutation in humans. These findings, which define a SF-1 mutation that apparently differentially affects its transcriptional activity in vivo in the adrenal cortex and the gonads, may be relevant to the cohort of patients who present with 46, XY sex reversal but normal adrenal function.
Steven A Kliewer - One of the best experts on this subject based on the ideXlab platform.
-
crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor 1
Molecular Cell, 2005Co-Authors: Yong Li, Mihwa Choi, Greg Cavey, Jennifer Daugherty, Kelly Suino, Amanda Kovach, Nathan C Bingham, Steven A Kliewer, Eric H XuAbstract:Abstract The orphan nuclear receptor steroidogenic factor 1 (SF-1) regulates the differentiation and function of Endocrine glands. Although SF-1 is constitutively active in cell-based assays, it is not known whether this transcriptional activity is modulated by ligands. Here, we describe the 1.5 A crystal structure of the SF-1 ligand binding domain in complex with an LXXLL motif from a coregulator protein. The structure reveals the presence of a phospholipid ligand in a surprisingly large pocket (∼1600 A 3 ), with the receptor adopting the canonical active conformation. The bound phospholipid is readily exchanged and modulates SF-1 interactions with coactivators. Mutations designed to reduce the size of the SF-1 pocket or to disrupt hydrogen bonds with the phospholipid abolish SF-1/coactivator interactions and significantly reduce SF-1 transcriptional activity. These findings provide evidence that SF-1 is regulated by endogenous ligands and suggest an unexpected relationship between phospholipids and Endocrine Development and function.
-
Crystallographic Identification and Functional Characterization of Phospholipids as Ligands for the Orphan Nuclear Receptor Steroidogenic Factor-1
Molecular Cell, 2005Co-Authors: Mihwa Choi, Greg Cavey, Jennifer Daugherty, Kelly Suino, Amanda Kovach, Nathan C Bingham, Steven A KliewerAbstract:The orphan nuclear receptor steroidogenic factor 1 (SF-1) regulates the differentiation and function of Endocrine glands. Although SF-1 is constitutively active in cell-based assays, it is not known whether this transcriptional activity is modulated by ligands. Here, we describe the 1.5 angstroms crystal structure of the SF-1 ligand binding domain in complex with an LXXLL motif from a coregulator protein. The structure reveals the presence of a phospholipid ligand in a surprisingly large pocket (approximately 1600 angstroms3), with the receptor adopting the canonical active conformation. The bound phospholipid is readily exchanged and modulates SF-1 interactions with coactivators. Mutations designed to reduce the size of the SF-1 pocket or to disrupt hydrogen bonds with the phospholipid abolish SF-1/coactivator interactions and significantly reduce SF-1 transcriptional activity. These findings provide evidence that SF-1 is regulated by endogenous ligands and suggest an unexpected relationship between phospholipids and Endocrine Development and function.