scholarly journals Deletion of Nuclear Receptor Constitutive Androstane Receptor CAR Increases Anxiety and Lowers Androgen Levels

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A807-A807
Author(s):  
Juan P Hernandez ◽  
Anjana Asokakumar ◽  
Rui Xiao ◽  
David D Moore ◽  
Sayeepriyadarshini Anakk
Keyword(s):  
Nuclear Receptor ◽  
Leydig Cells ◽  
Constitutive Androstane Receptor ◽  
Serum Testosterone ◽  
Transcriptional Networks ◽  
Testis Weight ◽  
Orphan Nuclear Receptor ◽  
Plus Maze ◽  
Marble Burying ◽  
Androgen Levels

Abstract The orphan nuclear receptor, Constitutive Androstane Receptor (CAR, NR1I3) is primarily known to regulate the transcriptional networks involved in detoxification. We have identified a novel extra-hepatic role of CAR in regulating androgen levels and modulating testis function. Previous data has revealed that CAR activation by estradiol and inactivation by androstanol suggests an intricate link between sex hormones and CAR. We investigated control wild type and CARKO mice and found that the serum testosterone and androstenedione levels were lower in the absence of CAR. As expected, we did not find any induction of the genes in the detoxification machinery including, Cyp3a, Cyp2b, Cyp2c family, Sult2a1 and Mrp. The decrease in the androgen levels in the CARKO mice is consistent with decrease in the anogenital distance, increased anxiety as measured by marble burying and elevated plus maze but no change in testis weight. H&E staining of CARKO mice shows accumulation of fat in the Leydig cells and lower numbers of Leydig cells which are in accordance with the loss of androgen levels. In addition, we will examine the consequence of reduced androgen and the hypothalamus-pituitary-gonadal axis in the CARKO mice.

LH Induces Orphan Nuclear Receptor Nur77 Gene Expression in Testicular Leydig Cells

Endocrinology ◽  
2001 ◽  
Vol 142 (12) ◽  
pp. 5116-5123 ◽  
Author(s):  
Kwang-Hoon Song ◽  
Jae-Il Park ◽  
Mi-Ock Lee ◽  
Jaemog Soh ◽  
Keesook Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Leydig Cells ◽  
Orphan Nuclear Receptor

Leydig cell resistance to the cytotoxic effect of ethylene dimethanesulphonate in the adult rat testis

1985 ◽  
Vol 105 (3) ◽  
pp. 311-NP ◽  
Author(s):  
I. D. Morris
Keyword(s):  
Seminal Vesicle ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Serum Testosterone ◽  
Male Rats ◽  
Cell Physiology ◽  
Testis Weight ◽  
Endocrine Activity ◽  
Adult Rat ◽  
Seminal Vesicle Weight

ABSTRACT Weekly doses of the Leydig cell cytotoxic ethylene dimethanesulphonate (EDS) were administered to adult male rats in an attempt to study the endocrine activity of the testis in the absence of Leydig cells. One week after the first dose serum testosterone and LH concentrations and seminal vesicle weights were close to levels in castrated rats and testicular human chorionic gonadotrophin (hCG) binding was severely depressed. These changes were maintained for a further week but subsequently began to return to, but did not achieve, control levels. After six weekly doses seminal vesicle weight and serum testosterone concentrations were significantly higher than in the castrated rats. Serum LH concentrations were declining towards control values at 4 weeks but had risen again at 6 weeks. Serum FSH concentrations were raised to about 50% of the value in castrated rats throughout the period studied. Testis weight and hCG binding, which initially fell, were partially restored at 6 weeks and spermatogenesis was recovering. The data show that responses of the testis to multiple doses of EDS are similar to those after a single dose. This apparent resistance indicates that the regenerating Leydig cells are functionally different from the mature Leydig cell. The similarities between the maturing Leydig cell seen after EDS destruction and those in the immature rat suggest that EDS will provide a valuable model for the investigation of Leydig cell physiology. J. Endocr. (1985) 105, 311–316

scholarly journals The Orphan Nuclear Receptor DAX-1 Functions as a Potent Corepressor of the Constitutive Androstane Receptor (NR1I3)

2012 ◽  
Vol 82 (5) ◽  
pp. 918-928 ◽  
Author(s):  
Elizabeth M. Laurenzana ◽  
Tao Chen ◽  
Malavika Kannuswamy ◽  
Brian E. Sell ◽  
Stephen C. Strom ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Constitutive Androstane Receptor ◽  
Orphan Nuclear Receptor

scholarly journals The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

2014 ◽  
Vol 53 (1) ◽  
pp. 43-55 ◽  
Author(s):  
Raifish E Mendoza-Villarroel ◽  
Mickaël Di-Luoffo ◽  
Etienne Camiré ◽  
Xavier C Giner ◽  
Catherine Brousseau ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Protein Interactions ◽  
Leydig Cells ◽  
Molecular Mechanisms ◽  
Direct Repeat ◽  
Testicular Descent ◽  
Mrna Levels ◽  
Orphan Nuclear Receptor ◽  
Protein Protein Interactions ◽  
Dna Precipitation

Insulin-like 3 (INSL3), a hormone produced by Leydig cells, regulates testicular descent during foetal life and bone metabolism in adults. Despite its importance, little is known about the molecular mechanisms controlling INSL3 expression. Reduced Insl3 mRNA levels were reported in the testis of mice deficient for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), an orphan nuclear receptor known to play critical roles in cell differentiation and lineage determination in several tissues. Although COUP-TFII-deficient mice had Leydig cell dysfunction and impaired fertility, it remained unknown whether Insl3 expression was directly regulated by COUP-TFII. In this study, we observed a significant decrease in Insl3 mRNA levels in MA-10 Leydig cells depleted of COUP-TFII. Furthermore, a −1087 bp mouse Insl3 promoter was activated fourfold by COUP-TFII in MA-10 Leydig cells. Using 5′ progressive deletions, the COUP-TFII-responsive element was located between −186 and −79 bp, a region containing previously uncharacterised direct repeat 0-like (DR0-like) and DR3 elements. The recruitment and direct binding of COUP-TFII to the DR0-like element were confirmed by chromatin immunoprecipitation and DNA precipitation assay respectively. Mutation of the DR0-like element, which prevented COUP-TFII binding, significantly decreased COUP-TFII-mediated activation of the −1087 bp Insl3 reporter in CV-1 fibroblast cells but not in MA-10 Leydig cells. Finally, we found that COUP-TFII cooperates with the nuclear receptor steroidogenic factor 1 (SF1) to further enhance Insl3 promoter activity. Our results identify Insl3 as a target for COUP-TFII in Leydig cells and revealed that COUP-TFII acts through protein–protein interactions with other DNA-bound transcription factors, including SF1, to activate Insl3 transcription in these cells.

scholarly journals cAMP-Induced Expression of the Orphan Nuclear Receptor Nur77 in MA-10 Leydig Cells Involves a CaMKI Pathway

2008 ◽  
Vol 30 (2) ◽  
pp. 134-145 ◽  
Author(s):  
L. J. Martin ◽  
N. Boucher ◽  
B. El-Asmar ◽  
J. J. Tremblay
Keyword(s):  
Nuclear Receptor ◽  
Leydig Cells ◽  
Orphan Nuclear Receptor ◽  
Induced Expression

scholarly journals MEF2 Is Restricted to the Male Gonad and Regulates Expression of the Orphan Nuclear Receptor NR4A1

2014 ◽  
Vol 28 (6) ◽  
pp. 886-898 ◽  
Author(s):  
Caroline Daems ◽  
Luc J. Martin ◽  
Catherine Brousseau ◽  
Jacques J. Tremblay
Keyword(s):  
Nuclear Receptor ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Sex Differentiation ◽  
Dominant Negative ◽  
Mrna Levels ◽  
Orphan Nuclear Receptor ◽  
Hormonal Stimulation ◽  
Regulatory Cascade ◽  
And Function

Abstract Leydig cell steroidogenesis is controlled by the pituitary gonadotropin LH that activates several signaling pathways, including the Ca2+/calmodulin kinase I (CAMKI) pathway. In other tissues, CAMKI regulates the activity of the myocyte enhancer factor 2 (MEF2) transcription factors. MEF2 factors are essential regulators of cell differentiation and organogenesis in numerous tissues but their expression and role in the mammalian gonad had not been explored. Here we show that MEF2 factors are expressed in a sexually dimorphic pattern in the mouse gonad. MEF2 factors are present in the testis throughout development and into adulthood but absent from the ovary. In the testis, MEF2 was localized mainly in the nucleus of both somatic lineages, the supporting Sertoli cells and the steroidogenic Leydig cells. In Leydig cells, MEF2 was found to activate the expression of Nr4a1, a nuclear receptor important for hormone-induced steroidogenesis. In these cells MEF2 also cooperates with forskolin and CAMKI to enhance Nr4a1 promoter activity via two MEF2 elements (−318 and −284 bp). EMSA confirmed direct binding of MEF2 to these elements whereas chromatin immunoprecipitation revealed that MEF2 recruitment to the proximal Nr4a1 promoter was increased following hormonal stimulation. Modulation of endogenous MEF2 protein level (small interfering RNA-mediated knockdown) or MEF2 activity (MEF2-Engrailed active dominant negative) led to a significant decrease in Nr4a1 mRNA levels in Leydig cells. All together, our results identify MEF2 as a novel testis-specific transcription factor, supporting a role for this factor in male sex differentiation and function. MEF2 was also positioned upstream of NR4A1 in a regulatory cascade controlling Leydig cell gene expression.

Sign in / Sign up

Export Citation Format

Share Document