DAX1 (DSS-AHC critical region on the X chromosome, gene 1) that is deleted in AHC deletion patients and mutated in AHC nondeletion patients. The DAX1 gene, also called NR0B1, encodes a member of the nuclear hormone receptor superfamily and displays a novel DNA-binding domain. The DAX1 gene product acts as a dominant-negative regulator of transcription mediated by the retinoic acid receptor
NCBI Summary:
This gene encodes a protein that contains a DNA-binding domain. The encoded protein acts as a dominant-negative regulator of transcription which is mediated by the retinoic acid receptor. This protein also functions as an anti-testis gene by acting antagonistically to Sry. Mutations in this gene result in both X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism.
General function
Nucleic acid binding, DNA binding, Transcription factor
Comment
The DAX-1 product acts as a dominant negative regulator of transcription mediated by the retinoic acid receptor. In addition, DAX-1 can block the first and rate-limiting step in steroid biosynthesis by repressing StAR (steroidogenic acute regulatory protein) expression.
Cellular localization
Nuclear
Comment
The DAX-1 protein, an unusual member of the nuclear hormone receptor, may act as a transcriptional repressor. It has been shown to both repress transcriptional activators by direct protein-protein interactions and to bind DNA hairpin structures and repress target genes (Goodfellow, et al. 1999).
Ovarian function
Germ cell development
Comment
Alterations at the DAX-1 locus constitute one of the causes of sex reversal in individuals with a normal 46,XY karyotype. Identification of males deleted for DSS suggested that the locus is not required for testis differentiation. Bardoni et al. (1994) proposed that DSS has a role in ovarian development and/or functions as a link between ovary and testis formation.
Expression regulated by
Steroids
Comment
Steroidogenic Factor 1 (SF1) regulates the expression of a number of steroidogenic genes and a putative SF1 response element (SF1-RE) in the DAX1 promoter which binds SF1 specifically (Vilain, et al., 1997)..
Mizusaki H, et al 2003 reported that Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the x chromosome, gene 1) gene transcription is regulated by wnt4 in the female developing gonad.
Dax-1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (NR0B1)] is an orphan nuclear receptor acting as a suppressor of Ad4 binding protein/steroidogenic factor 1 [Ad4BP/SF-1 (NR5A1)] and as an anti-Sry factor in the process of gonadal sex differentiation. The roles of these nuclear receptors in the differentiation of the gonads and the adrenal cortex have been established through studies of the mutant phenotype in both mice and humans. However, the mechanisms underlying transcriptional regulation of these genes remain largely unknown. Here, the authors examined the relationship between Dax-1 gene transcription and the Wnt4 pathway. Reporter gene analysis revealed that Dax-1 gene transcription was activated by beta-catenin, a key signal-transducing protein in the Wnt pathway, acting in synergy with Ad4BP/SF-1. Interaction between beta-catenin and Ad4BP/SF-1 was observed using yeast two-hybrid and in vitro pull-down assays. The region of Ad4BP/SF-1 essential for this interaction consists of an acidic amino acid cluster, which resides in the first helix of the ligand-binding domain. Mutation of the amino acid cluster impaired transcriptional activation of Dax-1 as well as interaction of Ad4BP/SF-1 with beta-catenin. These results were supported by in vivo observations using Wnt4 gene-disrupted mice, in which Dax-1 gene expression was decreased significantly in sexually differentiating female gonads. The aauthors thus conclude that Wnt4 signaling mediates the increased expression of Dax-1 as the ovary becomes sexually differentiated.
Ovarian localization
Primordial Germ Cell, Granulosa
Comment
Sato Y, et al 2003 reported immunolocalization of Nuclear Transcription Factors, DAX-1 and COUP-TF
II, in the Normal Human Ovary and Correlation with Adrenal 4 Binding Protein/
Steroidogenic Factor-1 Immunolocalization during the Menstrual Cycle.
Steroid synthesis in the human ovary is regulated by the temporal and spatial expression of enzymes
involved in each step of ovarian steroidogenesis. Recent studies have demonstrated that DAX-1 and
COUP-TFII negatively regulate adrenal 4 binding protein (Ad4BP)/steroidogenic factor-1
(SF-1)-dependent transcription of steroidogenic enzymes in experimental animals. In this study the
expression patterns of these proteins in human normal ovaries were examined using
immunohistochemistry and compared with those of steroidogenic enzymes. In the ovarian follicle
and corpora lutea, immunoreactive DAX-1 protein was detected predominantly in granulosa cells,
whereas COUP-TFII was identified in thecal cells. In granulosa cells, both immunoreactive DAX-1
and Ad4BP/SF-1 protein expression increased after the preantral follicular stage. DAX-1
immunoreactivity was relatively high compared with that of Ad4BP/SF-1 in all follicular stages
from premordial to nondominant. The increase in expression of Ad4BP/SF-1 immunoreactivity
between follicles in the preantral and dominant stages of follicular development was greater than
that in DAX-1 expression. In thecal cells, immunoreactive COUP-TFII was consistently elevated
throughout the menstrual cycle, whereas Ad4BP/SF-1 immunoreactivity increased according to the
development of the follicle. These results indicated that DAX-1 and COUP-TFII may play a role in
the modulation of Ad4BP/SF-1-dependent transcription of steroidogenic enzymes in different cell
types and follicular stages in normal cycling human ovaries.
Ikeda Y, et al 2001 reported that the comparative localization of Dax-1 and Ad4BP/SF-1 during
development of the hypothalamic-pituitary-gonadal axis suggests
their closely related and distinct functions.
Two nuclear receptors, Ad4BP/ SF-1 and Dax-1, are essential regulators for
development and function of the mammalian reproductive system. In the female, Dax-1 was strongly
expressed in the entire ovarian primordium from E12.5 until E14.5, and then
its expression level was decreased and limited to cells near the surface
epithelium between E17.5 and postnatal day 0 (P0). During postnatal
development of the testis, the variable staining of Dax-1 in Sertoli cells was
detected as early as P7 and Dax-1-expressing Leydig cells became rare. In the
postnatal ovary, Dax-1 expression was detected in granulosa cells with
variable staining intensity, and occasionally in interstitial cells.
Follicle stages
Comment
The DAX-1 gene has been involved in the dosage sensitive sex reversal (DSS) phenotype, a male-to-female sex-reversal syndrome due to the duplication of a small region of human chromosome Xp21. Dax-1 and Sry have been shown to act antagonistically in the mouse system, where increasing expression of the former leads to female development and increasing activity of the latter to male development. Although these data strongly implicate DAX-1 in sex determination, the mouse and human proteins appear to behave differently. Absence of DAX-1 is responsible for adrenal hypoplasia congenita, a human inherited disorder characterized by adrenal insufficiency and hypogonadotropic hypogonadism. Unlike human patients, Dax-1-deficient XY mice have normal levels of corticotropins and adrenal hormones but are sterile. Dax-1-deficient females are fertile (Goodfellow, et al. 1999).
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: targeted overexpression fertility: infertile - ovarian defect Comment: Duplication of this gene in murine specimens
leads to male-to-female sex reversal.