Porcupine-dependent Wnt signaling controls stromal proliferation and endometrial gland maintenance through the action of distinct WNTs.

Wnt signaling has been shown to be important in orchestrating proper development of the female reproductive tract. In the uterus, six members of the Wnt family are expressed in the neonatal endometrium and deletion of individual Wnt genes often leads to similar phenotypes, suggesting an interaction of these genes in uterine development and function. Furthermore, Wnts may have complementary functions, which could mask the identification of their individual functional role in single gene deletions. To circumvent this issue, we have generated a deletion of the Porcupine homolog within the female reproductive tract using progesterone receptor-Cre mice (PgrCre/+); preventing Wnt secretion from the producing cells. We show that Porcupine-dependent Wnt signaling, unlike previously reported, is dispensable for postnatal gland formation but is required for post-pubertal gland maintenance as well as for stromal cell proliferation. Furthermore, our results demonstrate that WNT7a is sufficient to restore post-pubertal endometrial gland formation. Although WNT5a did not restore gland formation, it rescued stromal cell proliferation; up-regulating several secreted factors including Fgf10 and Ihh. Our results further elucidate the roles of Wnt signaling in uterine development and function as well as provide an ideal system to address individual Wnt functions in the uterus.