The nuclear receptor SF-1 mediates sexually dimorphic expression of Mullerian Inhibiting Substance, in vivo

Development ◽  
1997 ◽  
Vol 124 (9) ◽  
pp. 1799-1807
Author(s):  
G. Giuili ◽  
W.H. Shen ◽  
H.A. Ingraham
Keyword(s):  
Binding Site ◽  
Nuclear Receptor ◽  
Gene Activation ◽  
Proximal Promoter ◽  
Specific Marker ◽  
Sexually Dimorphic ◽  
Orphan Nuclear Receptor ◽  
Müllerian Inhibiting Substance ◽  
Mullerian Inhibiting Substance

Mullerian Inhibiting Substance (MIS) functions to promote regression of the Mullerian duct during male development. Maintaining the sexually dimorphic pattern of MIS expression is essential for proper mammalian reproductive tract development. Here, we show that the intricate spatial and temporal pattern of MIS expression is directed by a remarkably small proximal promoter of only 180 base pairs in length. Expression of the MIS-human growth hormone transgene (MIS/GH) is restricted to Sertoli cells in embryonic testis and to granulosa cells of postnatal ovary, consistent with the known MIS expression pattern. The proximal MIS promoter is therefore sufficient to direct the initiation and the maintenance of MIS gene expression in both sexes. Moreover, in vivo MIS promoter activity requires an intact binding site for the orphan nuclear receptor SF-1. Taken together, these data strongly suggest that SF-1 directly activates MIS in embryonic and postnatal gonads. Consistent with the proposed role of SF-1 in mammalian sex-determination, our study provides physiological evidence that a SF-1 binding site is essential for gene activation of an embryonic testis-specific marker.

scholarly journals Sequence-Specific DNA Binding by the αNAC Coactivator Is Required for Potentiation of c-Jun-Dependent Transcription of the Osteocalcin Gene

2005 ◽  
Vol 25 (9) ◽  
pp. 3452-3460 ◽  
Author(s):  
Omar Akhouayri ◽  
Isabelle Quélo ◽  
René St-Arnaud
Keyword(s):  
Dna Binding ◽  
Binding Site ◽  
Gene Transcription ◽  
Osteoblastic Differentiation ◽  
Proximal Promoter ◽  
Osteoblastic Cells ◽  
Specific Marker ◽  
Osteocalcin Gene

ABSTRACT Since the c-Jun coactivator αNAC was initially identified in a differential screen for genes expressed in differentiated osteoblasts, we examined whether the osteocalcin gene, a specific marker of terminal osteoblastic differentiation, could be a natural target for the coactivating function of αNAC. We had also previously shown that αNAC can specifically bind DNA in vitro, but it remained unclear whether the DNA-binding function of αNAC is expressed in vivo or if it is required for coactivation. We have identified an αNAC binding site within the murine osteocalcin gene proximal promoter region and demonstrated that recombinant αNAC or αNAC from ROS17/2.8 nuclear extracts can specifically bind this element. Using transient transfection assays, we have shown that αNAC specifically potentiated the c-Jun-dependent transcription of the osteocalcin promoter and that this activity specifically required the DNA-binding domain of αNAC. Chromatin immunoprecipitation confirmed that αNAC occupies its binding site on the osteocalcin promoter in living osteoblastic cells expressing osteocalcin. Inhibition of the expression of endogenous αNAC in osteoblastic cells by use of RNA interference provoked a decrease in osteocalcin gene transcription. Our results show that the osteocalcin gene is a target for the αNAC coactivating function, and we propose that αNAC is specifically targeted to the osteocalcin promoter through its DNA-binding activity as a means to achieve increased specificity in gene transcription.

scholarly journals The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Christine V. Ichim ◽  
Dzana D. Dervovic ◽  
Lap Shu Alan Chan ◽  
Claire J. Robertson ◽  
Alden Chesney ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Nuclear Receptor ◽  
Hematopoietic Cell ◽  
Orphan Nuclear Receptor

scholarly journals Transcriptional repression of the gluconeogenic gene PEPCK by the orphan nuclear receptor SHP through inhibitory interaction with C/EBPα

2007 ◽  
Vol 402 (3) ◽  
pp. 567-574 ◽  
Author(s):  
Min Jung Park ◽  
Hee Jeong Kong ◽  
Hye Young Kim ◽  
Hyeong Hoe Kim ◽  
Joon Hong Kim ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Repression ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Regulatory Element ◽  
Direct Interaction ◽  
Orphan Nuclear Receptor ◽  
Hepatic Gluconeogenesis ◽  
Inhibitory Interaction

SHP (short heterodimer partner) is an orphan nuclear receptor that plays an important role in regulating glucose and lipid metabolism. A variety of transcription factors are known to regulate transcription of the PEPCK (phosphoenolpyruvate carboxykinase) gene, which encodes a rate-determining enzyme in hepatic gluconeogenesis. Previous reports identified glucocorticoid receptor and Foxo1 as novel downstream targets regulating SHP inhibition [Borgius, Steffensen, Gustafsson and Treuter (2002) J. Biol. Chem. 277, 49761–49796; Yamagata, Daitoku, Shimamoto, Matsuzaki, Hirota, Ishida and Fukamizu (2004) J. Biol. Chem. 279, 23158–23165]. In the present paper, we show a new molecular mechanism of SHP-mediated inhibition of PEPCK transcription. We also show that the CRE1 (cAMP regulatory element 1; −99 to −76 bp relative to the transcription start site) of the PEPCK promoter is also required for the inhibitory regulation by SHP. SHP repressed C/EBPα (CCAAT/enhancer-binding protein α)-driven transcription of PEPCK through direct interaction with C/EBPα protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPα and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. Taken together, these results suggest that SHP might regulate a level of hepatic gluconeogenesis driven by C/EBPα activation.

scholarly journals Orphan Nuclear Receptor NR4A1 Is a Negative Regulator of DHT-Induced Rat Preantral Follicular Growth

2012 ◽  
Vol 26 (12) ◽  
pp. 2004-2015 ◽  
Author(s):  
Kai Xue ◽  
Jia-yin Liu ◽  
Bruce D. Murphy ◽  
Benjamin K. Tsang
Keyword(s):  
Receptor Antagonist ◽  
Nuclear Receptor ◽  
Mrna Abundance ◽  
Orphan Nuclear Receptor ◽  
Follicular Growth ◽  
Preantral Follicle ◽  
Follicle Growth ◽  
Preantral Follicles

Abstract Nuclear receptor subfamily 4 group A member1 (NR4A1), an orphan nuclear receptor, is involved in the transcriptional regulation of thecal cell androgen biosynthesis and paracrine factor insulin-like 3 (INSL3) expression. Androgens are known to play an important regulatory role in ovarian follicle growth. Using a chronically androgenized rat model, a preantral follicle culture model and virus-mediated gene delivery, we examined the role and regulation of NR4A1 in the androgenic control of preantral follicular growth. In the present study, Ki67 staining was increased in preantral follicles on ovarian sections from 5α-dihydrotestosterone (DHT)-treated rats. Preantral follicles from DHT-treated rats cultured for 4 d exhibited increased growth and up-regulation of mRNA abundance of G1/S-specific cyclin-D2 (Ccnd2) and FSH receptor (Fshr). Similarly, DHT (1 μm) increased preantral follicular growth and Ccnd2 and Fshr mRNA abundance in vitro. The NR4A1 expression was high in theca cells and was down-regulated by DHT in vivo and in vitro. Forced expression of NR4A1 augmented preantral follicular growth, androstenedione production, and Insl3 expression in vitro. Inhibiting the action of androgen (with androgen receptor antagonist flutamide) or INSL3 (with INSL3 receptor antagonist INSL3 B-chain) reduced NR4A1-induced preantral follicular growth. Furthermore, NR4A1 overexpression enhanced DHT-induced preantral follicular growth, a response attenuated by inhibiting INSL3. In conclusion, DHT promotes preantral follicular growth and attenuates thecal NR4A1 expression in vivo and in vitro. Our findings are consistent with the notion that NR4A1 serves as an important point of negative feedback to minimize the excessive preantral follicle growth in hyperandrogenism.

scholarly journals The Nuclear Receptor Cofactor Receptor-Interacting Protein 140 Is a Positive Regulator of Amphiregulin Expression and Cumulus Cell-Oocyte Complex Expansion in the Mouse Ovary

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2923-2932 ◽  
Author(s):  
Jaya Nautiyal ◽  
Jennifer H. Steel ◽  
Meritxell M. Rosell ◽  
Evanthia Nikolopoulou ◽  
Kevin Lee ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Granulosa Cells ◽  
Cumulus Cell ◽  
Proximal Promoter ◽  
Dependent Manner ◽  
Camp Response Element ◽  
Response Element ◽  
Cumulus Expansion ◽  
Interacting Protein

The nuclear receptor cofactor receptor-interacting protein 140 (RIP140) is essential for cumulus cell-oocyte complex (COC) expansion, follicular rupture, and oocyte release during ovulation. The expression of many genes necessary for COC expansion is impaired in the absence of RIP140, but the studies herein document that their expression can be restored and COC expansion rescued by treatment with the epidermal growth factor (EGF)-like factor amphiregulin (AREG) both in vitro and in vivo. We demonstrate by several approaches that RIP140 is required for the expression of the EGF-like factors in granulosa cells, but the dependence of genes involved in cumulus expansion, including Ptgs2 Has2, Tnfaip6, and Ptx3, is indirect because they are induced by AREG. Treatment of granulosa cells with forskolin to mimic the effects of LH increases AREG promoter activity in a RIP140-dependent manner that 1) requires an intact cAMP response element in the proximal promoter region of the Areg gene and 2) involves its actions as a coactivator for cAMP response element-binding protein/c-Jun transcription factors. Although human chorionic gonadotropin and AREG coadministration is sufficient to restore ovulation fully in RIP140 heterozygous mice in vivo, both follicular rupture and ovulation remain impaired in the RIP140 null mice. Thus, we conclude that although the level of RIP140 expression in the ovary is a crucial factor required for the transient expression of EGF-like factors necessary for cumulus expansion, it also plays a role in other signaling pathways that induce follicular rupture.

scholarly journals OTX5 Regulates Pineal Expression of the Zebrafish REV-ERBα through a New DNA Binding Site

2008 ◽  
Vol 22 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Shin-ichi Nishio ◽  
Tomoko Kakizawa ◽  
Gilles Chatelain ◽  
Gérard Triqueneaux ◽  
Frédéric Brunet ◽  
...  
Keyword(s):  
Pineal Gland ◽  
Binding Site ◽  
Fluorescent Protein ◽  
Specific Gene ◽  
Orphan Nuclear Receptor ◽  
Cis Acting ◽  
Lower Vertebrates ◽  
Green Fluorescent ◽  
Zebrafish Embryogenesis

Abstract The pineal gland plays a central role in the photoneuroendocrine system and acts as a photosensory organ in lower vertebrates. The orphan nuclear receptor Rev-erbα (NR1D1) has previously been shown to be expressed in the pineal and to be regulated with a robust circadian rhythm during zebrafish embryogenesis. This early pineal expression is under the control of the transcription factor Orthodenticle homeobox 5 (Otx5). In this paper, we show that Otx5 regulates the second zfRev-erbα promoter, ZfP2. Despite the absence of a classical Otx-binding site within ZfP2, this regulation depends on the integrity of the Otx5 homeodomain. Mapping experiments as well as EMSAs show that this interaction between Otx5 and ZfP2 depends on a noncanonical bipartite Otx-binding site (GANNCTTA and TAAA) that we called pineal expression related element (PERE). We showed that PERE is necessary for pineal expression in vivo by injecting zebrafish embryos with wild type and mutated versions of zfRev-erbα promoter fused to green fluorescent protein. Interestingly, PERE is found upstream of other genes expressed in the pineal gland, suggesting that it may play an important role in governing pineal expression. Our data establish that PERE is a novel cis-acting element contributing to pineal-specific gene expression and to Otx target gene regulation.

scholarly journals Adrenocorticotropic Hormone Regulates the Activities of the Orphan Nuclear Receptor Nur77 through Modulation of Phosphorylation*

Endocrinology ◽  
1997 ◽  
Vol 138 (10) ◽  
pp. 4138-4146 ◽  
Author(s):  
Yanzhuang Li ◽  
Lester F. Lau
Keyword(s):  
Dna Binding ◽  
Nuclear Receptor ◽  
Binding Domain ◽  
Mitogen Activated Protein Kinase ◽  
Dna Binding Domain ◽  
Orphan Nuclear Receptor ◽  
Expression Of Genes ◽  
Acth Treatment ◽  
Mitogen Activated Protein

Abstract ACTH treatment of Y1 adrenocortical cells induces the synthesis of Nur77, an orphan nuclear receptor that can act as a potent trans-activator for such genes as 21-hydroxylase (CYP21). Nur77 has thus been proposed to be a mediator of ACTH action in activating the expression of genes that encode steroidogenic enzymes. Here we show that ACTH regulates the activity of Nur77 at the level of phosphorylation. ACTH induces the synthesis of transcriptionally active, DNA-binding Nur77 that is unphosphorylated at Ser354, which resides within the DNA-binding domain. By contrast, the Nur77 population that is constitutively present in Y1 cells is phosphorylated at Ser354 and does not bind DNA. Substitutions of Ser354 with negatively charged amino acids, such as Asp or Glu, dramatically decreased Nur77 DNA-binding and trans-activation activities, whereas mutation to the neutral Ala had no effect. Aside from phosphorylation within the DNA-binding domain, ACTH treatment does not induce modifications in the N- and C-terminal domains of Nur77 that significantly affect activity. Although the specific kinases that phosphorylate Nur77 in vivo are not known, the mitogen-activated protein kinase/pp90RSK pathway is not critical to Nur77 regulation. We propose that ACTH treatment of Y1 cells results in modulation of the activities of both kinases and phosphatases, which, in turn, regulate the activities of such transcription factors as Nur77.

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