Neonatal Uterine and Vaginal Cell Proliferation and Adenogenesis Are Independent of Estrogen Receptor 1 (ESR1) in the Mouse1

Abstract

Neonatal uterus and vagina express estrogen receptor 1 (ESR1) and respond mitogenically to exogenous estrogens. However, neonatal ovariectomy does not inhibit preweaning uterine cell proliferation, indicating that this process is estrogen independent. Extensive literature suggests that ESR1 can be activated by growth factors in a ligand-independent manner and drive uterine cell proliferation. Alternatively, neonatal uterine cell proliferation could be ESR1 independent despite its obligatory role in adult luminal epithelial proliferation. To determine ESR1's role in uterine and vaginal development, we analyzed cell proliferation, apoptosis, and uterine gland development (adenogenesis) in wild-type (WT) and Esr1 knockout (Esr1KO) mice from Postnatal Day 2 to Postnatal Day 60. Uterine and vaginal cell proliferation, apoptosis, and uterine adenogenesis were comparable in WT and Esr1KO mice before weaning. By Days 29-60, glands had regressed, and uterine cell proliferation was reduced in Esr1KO mice in contrast to continued adenogenesis and proliferation in WT. Apoptosis in Esr1KO uterine epithelium was not increased compared to WT at any age, indicating that differences in cell proliferation, rather than apoptosis, cause divergence of uterine size in these two groups at puberty. Similarly, vaginal epithelial proliferation was reduced, and the epithelium became atrophic in Esr1KO mice by 29 days of age and later in Esr1KO mice. These results indicate that preweaning uterine and vaginal development is ESR1 independent but becomes dependent on ESR1 by Day 29 on. It is not yet clear what mechanisms drive preweaning vaginal and uterine development, but ligand-independent activation of ESR1 is not involved.

Chlamydia muridarum Induction of Glandular Duct Dilation in Mice

“…Although there is an association of the use of the progesterone receptor modulators (as contraceptives) with inactive endometrium cyst-dilated glands in women (44), there has been no direct evidence of the induction of uterine horn/glandular duct dilation in mice by progesterone. On the contrary, 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). Since glandular duct dilation was detected 60 days after infection while the control mice pretreated similarly with progesterone but without infection failed to develop any significant glandular duct dilation (Fig.…”

“…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). Aged mice can spontaneously develop cystic endometrial hyperplasia (34), which involves dilation and proliferation of the glandular ducts.…”

Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

“…Growth of the functionalis endometrium involves proliferation of the luminal epithelium, GE, and stroma from stem cells in the underlying stratum basalis adjacent to the myometrium (44). The cyclical regeneration of glands in the functionalis endometrium may be similar to GE morphogenesis that occurs in the neonatal and prepubertal uterus (45,46). Conditional deletion of Foxa2 in the neonatal mouse immediately after birth completely inhibited GE differentiation in the neonatal mouse (4), establishing that Foxa2 is a key regulator of GE differentiation and growth before puberty.…”

Transdifferentiation of adult rat stem Leydig cells into prostatic and uterine epithelium, but not epidermis

“…Grafts were processed as described (Simon et al , 2009) and 6 µm sections were placed on slides, deparaffinized and subjected to antigen retrieval using citrate buffer (Nanjappa et al , 2015), followed by 20 mins in 0.9% hydrogen peroxide in methanol. Sections were washed in 0.05% tween-20 phosphate buffered saline (PBST) and incubated with blocking solution (goat serum solution provided in VECTASTAIN Elite ABC HRP kit [#PK6101, Vector Laboratories]) before overnight incubation at 4°C with primary antibodies in blocking buffer.…”