title: The partial female to male sex reversal in Wnt-4-deficient females involves induced expression of testosterone biosynthetic genes and testosterone production, and depends on androgen action.
abstract: Wnt-4 signaling has been implicated in female development, because its absence leads to partial female to male sex reversal in the mouse. Instead of Mullerian ducts, Wnt-4-deficient females have Wolffian ducts, suggesting a role for androgens in maintaining this single-sex duct type in females. We demonstrate here that testosterone is produced by the ovary of Wnt-4-deficient female embryos and is also detected in the embryonic plasma. Consistent with this, the expression of several genes encoding enzymes in the pathway leading to the synthesis of testosterone in the mouse is induced in the Wnt-4-deficient ovary, including Cyp11a, Cyp17, Hsd3b1, Hsd17b1, and Hsd17b3. Inhibition of androgen action with an antiandrogen, flutamide, during gestation leads to complete degeneration of the Wolffian ducts in 80% of the mutant females and degeneration of the cortical layer that resembles the tunica albuginea in the masculinized ovary. However, androgen action is not involved in the sexually dimorphic organization of endothelial cells in the Wnt-4 deficient ovary, because flutamide did not change the organization of the coelomic vessel. These data imply that Wnt-4 signaling normally acts to suppress testosterone biosynthesis in the female, and that testosterone is the putative mediator of the masculinization phenotype in Wnt-4-deficient females.
authors.affiliation: Biocenter Oulu, University of Oulu, Aapistie 5A, University of Oulu, P.O. Box 5000, FIN-90014 Oulu, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Heikkilä
authors.forename: Renata
authors.initials: R
authors.lastname: Prunskaite
authors.forename: Florence
authors.initials: F
authors.lastname: Naillat
authors.forename: Petri
authors.initials: P
authors.lastname: Itäranta
authors.forename: Jussi
authors.initials: J
authors.lastname: Vuoristo
authors.forename: Juhani
authors.initials: J
authors.lastname: Leppäluoto
authors.forename: Hellevi
authors.initials: H
authors.lastname: Peltoketo
authors.forename: Seppo
authors.initials: S
authors.lastname: Vainio
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D013196:Dihydrotestosterone / Q000378:metabolism; D012734:Disorders of Sex Development; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D010053:Ovary / Q000196:embryology / Q000201:enzymology*; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013739:Testosterone / Q000096:biosynthesis* / Q000097:blood; D051153:Wnt Proteins; D060528:Wnt4 Protein; D014928:Wolffian Ducts / Q000187:drug effects / Q000196:embryology
chemical_list: D000726:Androgen Antagonists; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D013196:Dihydrotestosterone; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme