MicroRNA-561 Promotes Acetaminophen-Induced Hepatotoxicity in HepG2 Cells and Primary Human Hepatocytes through Downregulation of the Nuclear Receptor Corepressor Dosage-Sensitive Sex-Reversal Adrenal Hypoplasia Congenital Critical Region on the X Chromosome, Gene 1 (DAX-1)

2013 ◽  
Vol 42 (1) ◽  
pp. 44-61 ◽  
Author(s):  
Minghua Li ◽  
Yinxue Yang ◽  
Zhi-Xu He ◽  
Zhi-Wei Zhou ◽  
Tianxin Yang ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
X Chromosome ◽  
Critical Region ◽  
Hepg2 Cells ◽  
Sex Reversal ◽  
Human Hepatocytes ◽  
Primary Human Hepatocytes ◽  
Chromosome Gene ◽  
Nuclear Receptor Corepressor ◽  
Adrenal Hypoplasia

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 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.

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