Postnatal Deletion of Wnt7a Inhibits Uterine Gland Morphogenesis and Compromises Adult Fertility in Mice.

Abstract

The success of postnatal uterine morphogenesis dictates, in part, the embryotrophic potential and functional capacity of the adult uterus. The definitive role of Wnt7a in postnatal uterine development and adult function requires a conditional knockout, because global deletion disrupts mü llerian duct patterning, specification, and cell fate in the fetus. The Wnt7a-null uterus appears to be posteriorized because of developmental defects in the embryo, as evidenced by the stratified luminal epithelium that is normally found in the vagina and the presence of short and uncoiled oviducts. To understand the biological role of WNT7A after birth and allow tissue-selective deletion of Wnt7a, we generated loxP-flanked exon 2 mice and conditionally deleted Wnt7a after birth in the uterus by crossing them with Pgr Cre mice. Morphological examination revealed no obvious differences in the vagina, cervix, oviduct, or ovary. The uteri of Wnt7a mutant mice contained no endometrial glands, whereas all other uterine cell types appeared to be normal. Postnatal differentiation of endometrial glands was observed in control mice, but not in mutant mice, between Postnatal Days 3 and 12. Expression of morphoregulatory genes, particularly Foxa2, Hoxa10, Hoxa11, Msx1, and Wnt16, was disrupted in the Wnt7a mutant uteri. Conditional Wnt7a mutant mice were not fertile. Although embryos were present in uteri of mutant mice on Day 3.5 of pregnancy, blastocyst implantation was not observed on Day 5.5. Furthermore, expression of several genes (Foxa2, Lif, Msx1, and Wnt16) was reduced or absent in adult Wnt7a-deleted uteri on Day 3.5 postmating. These results indicate that WNT7A plays a critical role in postnatal uterine gland morphogenesis and function, which are important for blastocyst implantation and fertility in the adult uterus.developmental biology, female reproductive tract, pregnancy, transgenic/knockout model, uterus

Forkhead box a2 (FOXA2) is essential for uterine function and fertility

“…Those uteri contained unimplanted blastocysts in which the trophectoderm was in clear apposition to an intact LE with no evidence of stromal cell decidualization. Similarly, mice lacking uterine glands do not express Lif and exhibit a defect in blastocyst implantation (12,(33)(34)(35)(36)(37)(38). Thus, uterine glands and, by inference, their secretions do not influence preimplantation embryo growth and development but are required for implantation and successful establishment and maintenance of pregnancy.…”

“…Lif-null and uterine-glandless mice (Pgr Cre mice with conditional deletion of Foxa2, Ctnbb1, Lef1, Wnt4, Wnt5a, or Wnt7a and also mice with progesterone-induced uterine gland knockout, PUGKO) all exhibit deficiencies in peri-implantation Lif expression and defects in blastocyst implantation (12,(33)(34)(35)(36)(37). Of note, blastocysts from UGKO mice are implantation competent when transferred into normal uteri (38).…”

The role of Wnt signaling members in the uterus and embryo during pre-implantation and implantation

“…In a study, conditional activation of β-catenin caused an increased amount of enlarged glands in the uterus, whereas upon ablation of β-catenin, the endometrium contained no glands [47]. β-catenin protein was present predominantly in the uterine epithelia and was not different between control and mutant uteri with Wnt7a depletion during postnatal development of mice [40].…”

“…It was found that, postnatal ablation of Wnt7a after birth in the mouse uterus caused infertility depending on disruption of endometrial gland morphogenesis. Although uterus histology was not affected by an experimental model of Wnt7a conditional null allele, mutant uteri lacked endometrial glands and as a result, implantation did not occur in the uteri of mutant mice [40]. Wnt4 was also shown to be associated with development of endometrial glands in mice [41].…”

“…Recent studies provide that Wnt signaling control endometrial gland formation and ablation of specific Wnt signaling components results in infertility due to implantation failure [40,41]. Canonical Wnt ligand Wnt7a was identified as one of the epithelial Wnt genes, since it was expressed only in endometrial LE [42].…”