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

Abstract

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.

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

“…SF-1-mediated P450arom expression. (18) Gurates et al also demonstrated that DAX-1 inhibits Ad4BP/SF-1-pathwaydependent P450arom expression in cultured human endometriotic glandular and endometrial stromal cells. (19) These in vitro studies clearly demonstrated the potentially pivotal roles of DAX-1 in the regulation of in situ steroidogenesis and steroid metabolism in human endometrium and its disorders, possibly through the inhibition of in situ steroid production.…”

“…(13) DAX-1 has also been demonstrated to repress Ad4BP/SF-1-mediated transactivation of other steroidogenic genes, (14,15) including genes for P450c17 and aromatase p450 (P450arom). (16)(17)(18) DAX-1 inhibits Ad4BP/SF-1 pathway-dependent P450arom expression in cultured human endometriotic and endometrial stromal cells. (19) In addition, DAX-1 interacts with both subtypes of estrogen receptors, ERγ and ERβ.…”

Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires β-catenin

“…This observation may reflect sexually dimorphic actions of ␤-catenin, or the fact that luteinizing hormone (rather than FSH) is the primary regulator of STAR in GCs (43). Dax1, a putative ␤-catenin target (30), can also selectively modulate Cyp19a1 over other steroidogenic enzymes (44). Thus, ␤-catenin signaling may contribute to differential production of estrogen and progesterone by gonadotropins during the reproductive cycle.…”

Teasing out the role of aromatase in the healthy and diseased testis

“…To extend on this, another orphan member of the nuclear receptor family, Dax-1, exhibits an inhibitory effect on PII aromatase gene expression in normal settings however in the absence of Dax-1 in rats, Leydig cell tumors develop and a concomitant increase in aromatase gene expression results. 117 The precise extracellular regulator(s) that lead to the interaction of orphan transcription factors to the SPRE remain unknown however two have been postulated: (1) IGF-1: can regulate aromatase gene by stimulating SF-1 binding to the SFRE on PII in rat Leydig cell tumors 106 and (2) TH/TH-receptor complex is able to compete with SF-1 in binding to the SFRE response element on PII in rats. 107 The second is cyclic AMP responsive element (CRE) 112,113 which contains 3 CRE-like sequences (position -335: TGA ACT CA, position -231: TGA AAT CA and position -169: TGC ACG Figure 1.…”