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

Hirofumi Mizusaki, Ken Kawabe, Tokuo Mukai, Etsuko Ariyoshi, Megumi Kasahara, Hidefumi Yoshioka, Amanda Swain, Ken-Ichirou Morohashi

研究成果: ジャーナルへの寄稿記事

109 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)507-519
ページ数13
ジャーナルMolecular Endocrinology
17
発行部数4
DOI
出版物ステータス出版済み - 4 1 2003

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X-Linked Genes
Chromosomes, Human, Pair 1
Gonads
Catenins
Steroidogenic Factor 1
Genes
Orphan Nuclear Receptors
Acidic Amino Acids
Sex Differentiation
Wnt Signaling Pathway
Adrenal Cortex
Cytoplasmic and Nuclear Receptors
Reporter Genes
Transcriptional Activation
Ovary
Yeasts
Ligands
Phenotype
Gene Expression
Amino Acids

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

これを引用

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. / Mizusaki, Hirofumi; Kawabe, Ken; Mukai, Tokuo; Ariyoshi, Etsuko; Kasahara, Megumi; Yoshioka, Hidefumi; Swain, Amanda; Morohashi, Ken-Ichirou.

:: Molecular Endocrinology, 巻 17, 番号 4, 01.04.2003, p. 507-519.

研究成果: ジャーナルへの寄稿記事

Mizusaki, Hirofumi ; Kawabe, Ken ; Mukai, Tokuo ; Ariyoshi, Etsuko ; Kasahara, Megumi ; Yoshioka, Hidefumi ; Swain, Amanda ; Morohashi, Ken-Ichirou. / 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. :: Molecular Endocrinology. 2003 ; 巻 17, 番号 4. pp. 507-519.
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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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AU - Kawabe, Ken

AU - Mukai, Tokuo

AU - Ariyoshi, Etsuko

AU - Kasahara, Megumi

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AU - Swain, Amanda

AU - Morohashi, Ken-Ichirou

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