Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/β-catenin synergy

被引:155
作者
Jordan, BK
Shen, JHC
Olaso, R
Ingraham, HA
Vilain, E
机构
[1] Univ Calif Los Angeles, Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Sch Med, Dept Pediat, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, Sch Med, Dept Urol, Los Angeles, CA 90095 USA
关键词
D O I
10.1073/pnas.1834480100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页码:10866 / 10871
页数:6
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