Uterine glands: development, function and experimental model systems

Abstract

Development of uterine glands (adenogenesis) in mammals typically begins during the early post-natal period and involves budding of nascent glands from the luminal epithelium and extensive cell proliferation in these structures as they grow into the surrounding stroma, elongate and mature. Uterine glands are essential for pregnancy, as demonstrated by the infertility that results from inhibiting the development of these glands through gene mutation or epigenetic strategies. Several genes, including forkhead box A2, beta-catenin and members of the Wnt and Hox gene families, are implicated in uterine gland development. Progestins inhibit uterine epithelial proliferation, and this has been employed as a strategy to develop a model in which progestin treatment of ewes for 8 weeks from birth produces infertile adults lacking uterine glands. More recently, mouse models have been developed in which neonatal progestin treatment was used to permanently inhibit adenogenesis and adult fertility. These studies revealed a narrow and well-defined window in which progestin treatments induced permanent infertility by impairing neonatal gland development and establishing endometrial changes that result in implantation defects. These model systems are being utilized to better understand the molecular mechanisms underlying uterine adenogenesis and endometrial function. The ability of neonatal progestin treatment in sheep and mice to produce infertility suggests that an approach of this kind may provide a contraceptive strategy with application in other species. Recent studies have defined the temporal patterns of adenogenesis in uteri of neonatal and juvenile dogs and work is underway to determine whether neonatal progestin or other steroid hormone treatments might be a viable contraceptive approach in this species.

Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

“…Loss of certain genes, such as Foxa2, Ctnnb1 (β-catenin), Wnt4, Wnt5a, Wnt7a, and Lef1, also results in reduction or absence of uterine glands (reviewed in ref. 28). In this study, N1ICD OEx mice also failed to develop their uterine glands, similar to the studies described above.…”

Chlamydia muridarum Induction of Glandular Duct Dilation in Mice

“…These observations and analyses together suggest that it is possible for C. muridarum to induce inflammatory blockage in the glandular duct and cause dilation of the glandular duct, finally resulting in visible uterine horn dilation that lasts for a long time (more than 60 days). Endometrial glands can be affected by hormones (30,35,44). In the current study, all mice were pretreated with progesterone 5 days prior to chlamydial infecton.…”

“…Mice undergo adenogenesis postnatally by budding from the lumenal epithelium (30). Progesterone has been shown to inhibit uterine gland development in the neonatal mouse uterus (31,32), while estrogen seems to be required for maintaining uterine gland function in adult mice (33).…”

Update of Wnt signaling in implantation and decidualization

“…Regulation of Wnt/PCP signaling was shown to get involved in normal pre-implantation development, as it appeared to enable clusters of developing blastocysts to be discriminated and form a single inner cell mass [54]. As a central mediator in propagating Wnt signaling to canonical and non-canonical pathways, all three murine Dsh genes (Dsh1, Dsh2, and Dsh3) were generally expressed with distinct spatio-temporal localizations in pre-implantation embryo [55][56][57]. The overexpression of Dsh-GFP fusion proteins caused a dramatic impair in the morphology and adhesion properties of four-cell stage mouse embryos, thereby leading to a lack of coherence in the generating blastocyst [56].…”