Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/β-catenin synergy
Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/β-catenin synergy
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DOI：
10.1073/pnas.1834480100
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发表时间：
2003-09-16
影响因子：
11.1
通讯作者：
Vilain, E
中科院分区：
文献类型：
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作者：
Jordan, BK;Shen, JHC;Vilain, E
对小鼠的遗传研究表明，Wnt 4信号传导拮抗雄性激素的表达，并有效地阻止雌性胚胎中的雄性发育。我们最近发现了一个XY中间性患者携带的WNT 4基因座的染色体重复，并提出，这个病人的女性化产生的WNT 4剂量增加。为了检验这一假设，产生了具有含有人WNT 4的大基因组P1的转基因小鼠。虽然在WNT 4转基因雄性小鼠中未观察到完全的雄性到雌性间性表型，但检测到类固醇生成急性调节蛋白的急剧减少与血清和睾丸雄激素水平的显著降低一致。此外，在WNT 4转基因雄性动物的睾丸中观察到生殖细胞轻度减少和血管系统紊乱。与这些体内数据一致，Wnt 4抑制肾上腺皮质和Leydig细胞系中的类固醇生成，如通过降低孕酮分泌和3 β-羟基类固醇脱氢酶活性所证明的。体外研究表明，Wnt 4拮抗Wnt信号通路的主要效应子β-连环蛋白和类固醇生成因子1之间观察到的功能协同作用，染色质免疫沉淀显示，Wnt 4减弱β-连环蛋白向类固醇生成急性调节蛋白启动子的募集。我们的研究结果表明，Wnt 4作为一种抗雄性因子的模型中，破坏招聘β-连环蛋白或附近的类固醇生成因子1结合位点存在于多个类固醇基因。
Genetic studies in mice suggest that Wnt4 signaling antagonizes expression of male hormones and effectively blocks male development in the female embryo. We recently identified an XY intersex patient carrying a chromosomal duplication of the WNT4 locus and proposed that this patient's feminization arises from an increased dosage of WNT4. To test this hypothesis, a transgenic mouse was generated with a large genomic P1 containing the human WNT4. Although a complete male to female intersex phenotype was not observed in WNT4 transgenic male mice, a dramatic reduction in steroidogenic acute regulatory protein was detected consistent with the marked reduction in serum and testicular androgen levels. Furthermore, a mild reduction of germ cells and a disorganized vascular system were observed in testes of WNT4 transgenic males. Consistent with these in vivo data, Wnt4 repressed steroidogenesis in adrenocortical and Leydig cell lines, as evidenced by reduced progesterone secretion and 3beta-hydroxysteroid dehydrogenase activity. In vitro studies showed that Wnt4 antagonizes the functional synergy observed between the major effector of the Wnt signaling pathway, beta-catenin and steroidogenic factor 1, and chromatin immunoprecipitation showed that Wnt4 attenuates recruitment of beta-catenin to the steroidogenic acute regulatory protein promoter. Our findings suggest a model in which Wnt4 acts as an anti-male factor by disrupting recruitment of beta-catenin at or near steroidogenic factor 1 binding sites present in multiple steroidogenic genes.