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.

Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals

“…WNT4 suppresses testosterone biosynthesis in the female mouse, inhibits the formation of the male-specific vascularization in the ovary and represses migration of endothelial and steroidogenic cells from the mesonephros and adrenal anlagen to the ovary, this suggesting an anti-testis and pro-ovary function. [20][21][22] Furthermore, WNT4 is likely to play a role in follicle development and maturation. 23,24 WNT4 seems to exert its functions via the upregulation of follistatin, a signaling molecule that binds to members of the transforming growth factor β family of proteins, as suggested by expression and null mutation analysis.…”

WNT4 is expressed in human fetal and adult ovaries and its signaling contributes to ovarian cell survival

“…Wnt4 +/-mice in SV129 background were crossed to obtain -/-embryos and the genotypes were analyzed as described earlier (Heikkila et al 2005, Stark et al 1994. Female wild-type and Wnt4-deficient mouse embryos aged 12.5, 14.5 and 16.5 dpc and newborn animals were studied.…”

“…Female mutant mice lack Müllerian ducts and have male-type Wolffian ducts instead (Vainio et al 1999). In addition to their masculinized appearance, mutant ovaries express many Leydig and Sertoli cell markers and secrete testosterone and Müllerian-inhibiting substance (MIS) (Heikkila et al 2001, Heikkila et al 2005.…”

Genetic aspects of vagina and the uterus aplasia: the history

“…При делеции гена Emx2 также наблюдалось полное отсутствие развития мочеполо-вой системы у нокаутной мыши [33]. Что касается гена Wnt4, экспрессирующегося мезенхимальными клетками, окружающими зачатки МП, то у нокаут-ной по этому гену мыши отсутствовали половые ор-ганы и была выражена маскулинизация [34]. Мута-ции гена Wnt4 у человека приводят к аплазии матки и влагалища.…”