Potential Role of Wnt in Neonatal Uterine Development.

WNT genes encode secreted glycoproteins that control cell fate, mortality, proliferation, differentiation, and tissue growth, and subsets (Wnt4, Wnt5a, and Wnt7a) are involved in Mullerian duct patterning and differentiation during embryonic development of the female reproductive tract. The present study investigated potential role of Wnts during postnatal mouse uterine development, because disruption of endometrial adenogenesis and mesenchymal specification and differentiation can cause permanent fertility problems in the adult. The expression of 19 Wnt genes and 10 Fzd receptors was determined by RT-PCR. The spatial expression patterns of the most highly expressed genes: Wn4, Wnt5a, Wnt7a, Wnt7b, Wnt11, Wnt16, Fzd6 and Fzd10 were further examined by in situ hybridization in the neonatal mouse uterus. Wnt4, Wnt5a and Wnt16 were localized in the endometrial stroma, whereas Wnt7a, Wnt7b and Wnt11 were in the uterine epithelia of neonatal mice. Exposure of mice to estrogen or progesterone during critical development periods inhibits endometrial adenogenesis. Diethylstilbestrol (DES) or progesterone-induced disruption of endometrial gland development was associated with reduction or ablation of Wn4, Wnt5a, Wnt7a, Wnt11, Wnt16 and Fzd10 mRNA during endometrial morphogenesis. Next, we have characterized postnatal uterine morphogenesis by conditionally ablating the expression of Wnt11 in the uterine epithelium of mouse after birth using progesterone receptor (PR) Cre knockin mouse. To increase the efficiency in the production of homozygous null alleles and to decrease the incidence of mosaic deletion, PRcre/+ Wnt11f/- mice were crossed with PRcre/+Wnt11+/- mice to PR+/+Wnt11f/f mice. Wnt11d/d mice did not show disrupted endometrial gland development, and adult Wnt11d/d mice had normal estrus cycles and were fertile. However, we observed disorganized luminal epithelium on postnatal (P) day 7 in Wnt11d/d mice, and levels of Wnt4, Wnt5a, Wnt7a, Wnt7b and Wnt16 in neonatal uteri were decreased in Wnt11d/d mice compared to those in Wnt11f/f mice. Interestingly, ablation of Wnt11 appears to increase the numbers of endometrial glands on P21 and P28. Wnt7a was stimulated on P14 and P21 in uteri of Wnt11f/f mice, whereas Wnt5a and Wnt16 were suppressed by loss of Wnt11. These results implicate that temporal and spatial expression of Wnts are critical factors for endometrial adenogenesis via autocrine and paracrine effects on neonatal uterine development. Further, Wnt11 actions may involve changes in the expression of other members of the Wnt system to regulate uterine morphogenesis. Supported by NIH HD058222. (platform)