scholarly journals 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

2003 ◽  
Vol 17 (4) ◽  
pp. 507-519 ◽  
Author(s):  
Hirofumi Mizusaki ◽  
Ken Kawabe ◽  
Tokuo Mukai ◽  
Etsuko Ariyoshi ◽  
Megumi Kasahara ◽  
...  
Keyword(s):  
Amino Acid ◽  
Gene Transcription ◽  
X Chromosome ◽  
Transcriptional Activation ◽  
Critical Region ◽  
Sex Reversal ◽  
Adrenal Hypoplasia Congenita ◽  
Chromosome Gene ◽  
Adrenal Hypoplasia ◽  
Amino Acid Cluster

Abstract 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, we examined the relationship between Dax-1 gene transcription and the Wnt4 pathway. Reporter gene analysis revealed that Dax-1 gene transcription was activated by β-catenin, a key signal-transducing protein in the Wnt pathway, acting in synergy with Ad4BP/SF-1. Interaction between β-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 β-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. We thus conclude that Wnt4 signaling mediates the increased expression of Dax-1 as the ovary becomes sexually differentiated.

scholarly journals The Effects of Estrogen on the Expression of Genes Underlying the Differentiation of Somatic Cells in the Murine Gonad

Endocrinology ◽  
2004 ◽  
Vol 145 (8) ◽  
pp. 3950-3960 ◽  
Author(s):  
Kara L. Britt ◽  
Peter G. Stanton ◽  
Marie Misso ◽  
Evan R. Simpson ◽  
Jock K. Findlay
Keyword(s):  
Cell Differentiation ◽  
Somatic Cell ◽  
X Chromosome ◽  
Critical Region ◽  
Leydig Cells ◽  
Hydroxysteroid Dehydrogenase ◽  
Sex Reversal ◽  
Steroidogenic Factor 1 ◽  
Chromosome Gene ◽  
Adrenal Hypoplasia

Abstract Estrogen (17β-estradiol, E2)-deficient aromatase knockout (ArKO) mice develop Sertoli and Leydig cells at puberty. We hypothesized that estrogen, directly or indirectly, regulates genes responsible for somatic cell differentiation and steroidogenesis. ArKO ovaries expressed estrogen receptors α and β, and LH receptor, indices of estrogen responsiveness in the ovary. Wild-type (Wt) and ArKO mice received either E2 or placebo for 3 wk, from 7–10 wk of age. E2 decreased serum FSH and LH and increased uterine weights of 10-wk-old ArKO mice. We measured mRNA expression of Sertoli cell, Sry-like HMG box protein 9 (Sox9); three upstream transcription factors, liver receptor homolog-1 (Lrh-1), steroidogenic factor 1, and dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome gene 1; and one downstream factor, Müllerian-inhibiting substance. Placebo-treated ArKO ovaries have increased Sox9 (15-fold; P < 0.001), Müllerian-inhibiting substance (2.9-fold), Lrh-1 (7.7-fold), and dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome gene 1 (12-fold) expression compared with Wt at 10 wk. Steroidogenic factor 1 was similar to Wt. Consistent with increased serum T levels and Leydig cells in their ovaries, placebo-treated ArKO ovaries had increased 17α-hydroxylase, 17β-hydroxysteroid dehydrogenase type-3, and 17β-hydroxysteroid dehydrogenase type-1 expression compared with Wt at 10 wk. E2 treatment for 3 wk improved the ovarian phenotype, decreased development of Sertoli cells, decreased the expression of Sox9, Lrh-1, and the steroidogenic enzymes in ArKO ovaries, and induced ovulation in some cases. In conclusion, the expression of the genes regulating somatic cell differentiation is directly or indirectly responsive to estrogen.

scholarly journals Investigation of Epigenetic Control of DAX-1 Expression in Human Cell Lines

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A506-A507
Author(s):  
Caroline P Riedstra ◽  
Christina Tzagarakis-Foster
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
X Chromosome ◽  
Sex Reversal ◽  
Nuclear Hormone Receptor ◽  
Molecular Techniques ◽  
Enzyme Analysis ◽  
Epigenetic Control ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

Abstract Dosage-Sensitive Sex Reversal, Adrenal Hypoplasia Congenita, Critical Region on the X chromosome, gene 1 (DAX-1 or NR0B1) is an orphan nuclear hormone receptor implicated in Adrenal Hypoplasia Congenita (AHC) and Dosage Sensitive Sex Reversal (DSS). In both instances, DAX-1 plays a key role in growth and development by modulating hormone function. In DSS, mutations on the X-chromosome lead to duplication of the region containing DAX-1, resulting in sex reversal, and in AHC, mutations in the DAX-1 gene diminish development of adrenal tissue which leads to a reduction in adrenal hormone production. Expressed predominantly in tissues such as the testes, ovaries, breast, adrenal cortex, and lung, DAX-1 may serve as an indicator of aberrant growth. Here we hypothesize that DAX-1 is epigenetically regulated, specifically in cancer cells, thereby reducing its expression. We surveyed various human cancer cells in order to determine whether inhibiting DNA methylating enzymes released epigenetic control of the DAX-1 gene, resulting in an increase in expression. By implementing molecular techniques, such as bisulfite sequencing, we determined the precise methylation sites in the DAX-1 gene. Additionally, we carried out methylation specific restriction enzyme analysis to differentiate degrees of methylation between lung, breast, liver, cervical, and adrenal carcinoma cell lines. Following confirmation of the precise methylation sites, we utilized chromatin immunoprecipitation (ChIP) in order to identify the modifying proteins present on the DAX-1 CpG islands. In conjunction with these experimental techniques, we implemented a bioinformatics approach to analyze methylation in the promoter region of the DAX-1 gene across tissue sample data acquired from The Cancer Genome Atlas Program. The results of this research could lead to a translational application of understanding where this orphan NHR fits into the development and progression of cancer. As a quickly growing field, cancer epigenetics is a key player in the ongoing pursuit for identifying biomarkers that may be pertinent in future therapeutic applications.

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