Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function

Swain, Amanda; Zanaria, Elena; Hacker, Adam; Lovell-Badge, Robin; Camerino, Giovanna

doi:10.1038/ng0496-404

Cited by 369 publications

(197 citation statements)

References 36 publications

Supporting

Mentioning

177

Contrasting

Unclassified

Order By: Relevance

“…In ovary, ER␤ is mainly expressed in granulosa cells, whereas ER␣ expression is much lower and restricted to interstitial theca cells. Although a comparative analysis of DAX protein expression needs to be accomplished, the known mRNA expression pattern suggests DAX-1 coexpression in all of these cell types (22,29,31,32,35). Notably, until now little is known about female-specific roles of DAX-1.…”

Section: Discussionmentioning

confidence: 99%

DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors

Zhang¹,

Thomsen

Johansson

et al. 2000

Journal of Biological Chemistry

155

127

View full text Add to dashboard Cite

We have discovered that the orphan receptor DAX-1 (NROB1) interacts with the estrogen receptors ER␣ and ER␤. Interaction occurs with ligand-activated ERs in solution and on DNA and is mediated by the unique DAX-1 N-terminal repeat domain. Each of the three repeats contains a leucine-rich receptor-binding motif, known as the LXXLL motif, which is usually found in nuclear receptor coactivators. We have demonstrated that DAX-1 functions as an inhibitor of ER activation in mammalian cells and suggest a mechanism involving two sequential events, occupation of the ligand-induced coactivator-binding surface and subsequent recruitment of corepressors. Accordingly, we propose that DAX-1 itself acts as a corepressor for ERs. Because DAX-1 is coexpressed with ERs in reproductive tissues, these interactions could play significant roles by influencing estrogen signaling pathways. Our results point at functional similarities between DAX-1 and the orphan receptor SHP (NROB2) in that they have acquired features of transcriptional coregulators that are unique for members of the nuclear receptor family.To transduce hormone and metabolic signaling to target genes, nuclear receptors require transcriptional cofactors that are collectively referred to as coregulators (1). These proteins exist in multiple complexes, possess multiple enzymatic activities, and bridge receptors to chromatin components or to the basal transcription machinery or to both. Multiple candidate proteins exist that are believed to be critical for the proper function of nuclear receptor signaling (1-3). The majority of coregulators bind to the receptor ligand-binding domain (LBD), 1 which is able to adopt different conformations depending on the ligand status and thereby discriminate between coactivators and corepressors. Functional and structural studies in particular elucidated the precise mechanisms of coactivator interaction with the ligand-inducible activation domain (AF-2) via short leucine motifs known as LXXLL or NR-Box (4 -8).We became interested in coregulators in particular that influence the transcriptional activity of estrogen receptors (ER). Two related subtypes, ER␣ and ER␤, play crucial roles in sex development and reproduction in multiple physiological processes as well as in cancer (9 -11). Previous research has provided detailed insights into structural and functional aspects of their interplay with coregulators (8,(12)(13)(14). Although agonist binding usually is associated with ER activation caused by coactivator recruitment, regulatory mechanisms have been proposed that could play a role in modulation and feedback control of estrogen signaling (15, 16). Recent work has revealed an unexpected role of the orphan receptor SHP (NROB2) in inhibiting transactivation of ERs (17, 18). Particularly, we have provided evidence that SHP, which consists only of an LBD and thus cannot bind target genes directly, has instead acquired a novel coregulator function by antagonizing the interactions of ERs with associated coactivators (18,19).The closest relati...

show abstract

Section: Discussionmentioning

confidence: 99%

DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors

Zhang¹,

Thomsen

Johansson

et al. 2000

Journal of Biological Chemistry

155

127

View full text Add to dashboard Cite

show abstract

“…Leydig cells were purified from the nonadherent crude interstitial cells by centrifugation (Sorvall HB-4 rotor, 57,000 rpm ϫ 5 min) through an 11-23% metrizamide density gradient and resuspended in serum-free DMEM͞ F12 medium supplemented with 2.2 g/liter sodium bicarbonate͞10 mM Hepes, pH 7.4͞500 ng/ml insulin͞100 units/ml penicillin͞100 g/ml streptomycin͞1 mg/ml BSA. Cells were plated at a density of 1 ϫ 10 5 cells per cm 2 and incubated in a humidified atmosphere of 5% CO 2 at 32°C. The Leydig cell preparations were determined to be Ϸ90% pure by using immunohistochemical staining for 3␤-HSD (20).…”

Section: Methodsmentioning

confidence: 99%

“…D AX-1 [dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1] is an orphan member of the nuclear hormone receptor superfamily of transcription factors (1)(2)(3). Duplication of the region on the X chromosome containing the DAX1 gene is associated with male-to-female sex reversal in XY individuals (1).…”

mentioning

confidence: 99%

Aromatase ( Cyp19 ) expression is up-regulated by targeted disruption of Dax1

Wang

Jeffs²,

Ito³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

127

View full text Add to dashboard Cite

DAX-1 [dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1] is an orphan nuclear receptor that represses transcription by steroidogenic factor-1 (SF-1), a factor that regulates expression of multiple steroidogenic enzymes and other genes involved in reproduction. Mutations in the human DAX1 gene (also known as AHC) cause the X-linked syndrome AHC, a disorder that is associated with hypogonadotropic hypogonadism also. Characterization of Dax1-deficient male mice revealed primary testicular defects that included Leydig cell hyperplasia (LCH) and progressive degeneration of the germinal epithelium, leading to infertility. In this study, we investigated the effect of Dax1 disruption on the expression profile of various steroidogenic enzyme genes in Leydig cells isolated from Dax1-deficient male mice. Expression of the aromatase (Cyp19) gene, which encodes the enzyme that converts testosterone to estradiol, was increased significantly in the Leydig cells isolated from mutant mice, whereas the expression of other proteins (e.g., StAR and Cyp11a) was not altered. In in vitro transfection studies, DAX-1 repressed the SF-1-mediated transactivation of the Cyp19 promoter but did not inhibit the StAR or Cyp11a promoters. Elevated Cyp19 expression was accompanied by increased intratesticular levels of estradiol. Administration of tamoxifen, a selective estrogen-receptor modulator, restored fertility to the Dax1-deficient male mice and partially corrected LCH, suggesting that estrogen excess contributes to LCH and infertility. Based on these in vivo and in vitro analyses, aromatase seems to be a physiologic target of Dax-1 in Leydig cells, and increased Cyp19 expression may account, in part, for the infertility and LCH in Dax1-deficient mice.

show abstract

“…(5) DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family. (6,7) DAX-1 is expressed in the adrenal cortex, ovary, Leydig cells and other endocrine cells such as testicular Sertoli cells, pituitary gonadotropes, ventromedial hypothalamic nucleus cells and others. (8,9) DAX-1 acts as a negative regulator of steroid production by repressing the expression of steroidogenic acute regulatory protein (StAR) in the adrenal cortex and gonads, (10)(11)(12) side-chain cleavage P450 (P450scc) and 3β-hydoroxysteroid dehydrogenase (3β-HSD).…”

mentioning

confidence: 99%

Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Saito¹,

Itō²,

Suzuki³

et al. 2005

Cancer Science

View full text Add to dashboard Cite

DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family. DAX-1 functions as a global negative regulator of steroid hormone production. It inhibits adrenal 4 binding protein (Ad4BP)/steroidogenic factor-1 (SF-1) pathway-dependent P450arom expression in cultured human endometriotic stromal cells and acts as a corepressor for estrogen receptors (ER). In this study we first examined the localization of DAX-1 in 46 normal cycling endometria, 36 cases of endometrial hyperplasia and 103 cases of endometrial carcinoma by using immunohistochemistry to elucidate the possible involvement of DAX-1 and its correlation to the status of Ad4BP/SF-1, a universal transcription factor of steroidogenesis. We then evaluated DAX-1 mRNA expression, using quantitative reverse transcription-polymerase chain reaction for DAX-1 in 33 cases of endometrial carcinoma for further characterization. We subsequently correlated these findings with various clinicopathological parameters of the cases. Ad4BP/SF-1 immunoreactivity was not detected in any human endometria examined. A significant inverse correlation was detected between the status of DAX-1 immunoreactivity and histological grade (P = 0.0003) in endometrial carcinoma. The labeling index (LI) values of DAX-1 in normal endometrium during the secretory phase (P < 0.0001) and hyperplasia (P < 0.0001) were significantly higher than that of carcinoma. No significant correlations were detected between DAX-1 immunoreactivity and amounts of aromatase mRNA. There was a statistically significant positive correlation between DAX-1 and ERα α α α (P = 0.006) and ERβ β β β LI (P < 0.001). These findings suggest that DAX-1 may inhibit the proliferation and progression of endometrial carcinoma through inhibition of estrogenic actions, possibly by interacting with ER present in carcinoma cells, rather than regulating in situ steroidogenesis. (Cancer Sci 2005; 96: 645-652) E ndometrial carcinoma is one of the most common pelvic malignancies among women worldwide, and its incidence has recently increased.(1,2) In situ estrogen metabolism, including synthesis and degradation, has been recently recognized as a very important factor in the development and progression of various human estrogen-dependent neoplasms, including endometrial carcinoma, especially the endometrioid type. (3,4) In endometrial carcinoma, in situ 17β-estradiol (E2) availability has been reported to be closely associated with the pathogenesis and development of endometrial proliferative disorders including endometrial hyperplasia and carcinoma, especially the endometrioid type.(5) DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family.(6,7) DAX-1 is expressed in the adrenal cortex, ovary, Leydig cells and other endocrine cells such as testicular Sertoli cells, pituitary gonadotropes, vent...

show abstract

Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function

Cited by 369 publications

References 36 publications

DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors

DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors

Aromatase ( Cyp19 ) expression is up-regulated by targeted disruption of Dax1

Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Contact Info

Product

Resources

About