Loss of function of the maternal membrane oestrogen receptor ERα alters expansion of trophoblast cells and impacts mouse fertility

Abstract

The binding of 17β-oestradiol to oestrogen receptor alpha (ERα) plays a crucial role in the control of reproduction, acting through both nuclear and membrane-initiated signalling. To study the physiological role of membrane ERα in the reproductive system, we used the C451A-ERα mouse model with selective loss of function of membrane ERα. Despite C451A-ERα mice being described as sterile, daily weighing and ultrasound imaging revealed that homozygous females do become pregnant, allowing the investigation of the role of ERα during pregnancy for the first time. All neonatal deaths of the mutant offspring mice resulted from delayed parturition associated with failure in pre-term progesterone withdrawal. Moreover, pregnant C451A-ERα females exhibited partial intrauterine embryo arrest at about E9.5. The observed embryonic lethality resulted from altered expansion of Tpbpa-positive spiral artery-associated trophoblast giant cells into the utero-placental unit, which is associated with an imbalance in expression of angiogenic factors. Together, these processes control the trophoblast-mediated spiral arterial remodelling. Hence, loss of membrane ERα within maternal tissues clearly alters the activity of invasive trophoblast cells during placentogenesis. This previously unreported function of membrane ERα could open new avenues towards a better understanding of human pregnancy-associated pathologies.

Role of membrane estrogen receptor alpha on the positive feedback of estrogens on LH secretion

“…However, it is also possible that E 4 impairs embryonic development as the absence of membrane signaling of ERα was recently shown to interfere with placentation leading to infertility (39).…”

“…Although this infertility largely relies on placental defects during development (39), this model offers the opportunity to assess the role of membrane-initiated action of ERα on the positive feedback of estrogens. Second, estetrol (E 4 ) is an estrogen exclusively synthesized in human fetal liver which selectively binds ERs (ERα and ERβ) but with a lower affinity than E 2 (40).…”

“…Similar observations were reported in the nuclear-only ERα (NOER) mice in which vaginal smears did not show the cornified epithelial cells typically observed during estrus (Pedram et al, 2014). Although this infertility largely relies on placental defects during development (39), this model offers the opportunity to assess the role of membrane-initiated action of ERα on the positive feedback of estrogens. Second, estetrol (E 4 ) is an estrogen exclusively synthesized in human fetal liver which selectively binds ERs (ERα and ERβ) but with a lower affinity than E 2 (40).…”

Estrogen Receptor Alpha Splice Variants, Post-Translational Modifications, and Their Physiological Functions

“…This mutation leads to female infertility [ 73 , 74 ]. Detailed reproduction phenotyping revealed that the C451A ERα mutant female mice can be pregnant but show a series of reproduction-associated abnormalities such as embryonic/neonatal death, delayed parturition, and small litter size [ 89 ]. This study showed abnormal placental development including altered behavior of a trophoblast cell population, which supports placentation and nourishes embryos.…”

“…Taken together, these observations indicate that membrane-bound ERα by palmitoylation on C451 is important to support female reproduction, from an endocrine mechanism and placenta development. Although membrane-initiated ERα signaling is involved in estrogen-mediated energy homeostasis [ 90 , 91 , 92 ], C451A ERα mutant mice do not show body weight phenotype and abnormal fat accumulation [ 74 , 75 , 89 ]. E 2 prevents bone demineralization, which is significantly impaired in the mutant mice, indicating that this effect is primarily exerted by membrane-bound ERα [ 75 ].…”