Targeted ablation of Wnt4and Wnt5ain Müllerian duct mesenchyme impedes endometrial gland development and causes partial Müllerian agenesis†

Wnt4and Wnt5ahave well-established roles in the embryonic development of the female reproductive tract, as well as in implantation, decidualization, and ovarian function in adult mice. Although these roles appear to overlap, whether Wnt5aand Wnt4are functionally redundant in these tissues has not been determined. We addressed this by concomitantly inactivating Wnt4and Wnt5ain the Müllerian mesenchyme and in ovarian granulosa cells by crossing mice bearing floxed alleles to the Amhr2crestrain. Whereas fertility was reduced by ∼50% in Wnt4flox/flox; Amhr2cre/+and Wnt5aflox/flox; Amhr2cre/+females, Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+mice were either nearly or completely sterile. Loss of fertility was not due to an ovarian defect, as serum ovarian hormone levels, follicle counts, and ovulation rates were comparable to controls. Conversely, the uterus was abnormal in Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+mice, with thin myometrial and stromal layers, frequent fibrosis and a >90% reduction in numbers of uterine glands, suggesting redundant or additive roles of Wnt4and Wnt5ain uterine adenogenesis. Loss of fertility in Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+mice was attributed to defects in decidualization, implantation, and placental development, the severity of which were proportional to the extent of gland loss. Furthermore, a third of Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+females had a partial agenesis of Müllerian duct-derived structures, but with normal oviducts and ovaries. Together, our results suggest that Wnt4and Wnt5aplay redundant roles in the development of the female reproductive tract, and may provide insight into the etiology of certain cases of Müllerian agenesis in women.