Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy.
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.
Jordan
Brian K
BK
Department of Human Genetics, University of California School of Medicine, Los Angeles, CA 90095-7088, USA.
Shen
Jennifer H-C
JH
Olaso
Robert
R
Ingraham
Holly A
HA
Vilain
Eric
E
D001483:Base Sequence; D015153:Blotting, Western; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D013737:Testis / Q000098:blood supply* / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D051153:Wnt Proteins; D060528:Wnt4 Protein; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; C515057:NR5A1 protein, human; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D051176:beta Catenin; C515058:steroidogenic factor 1, mouse; D013739:Testosterone