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.
Estrogens act through nuclear and membrane-initiated signaling. Estrogen receptor alpha (ERα) is critical for reproduction, but the relative contribution of its nuclear and membrane signaling is unclear. To address this question, we used two complementary approaches: estetrol (E4) a natural estrogen described to act as an agonist of nuclear ERα and a mERα antagonist and the C451A-ERα mouse lacking mERα. E4 dose-dependently blocks ovulation in female rats, but the mechanism underlying this effect is unknown. To determine whether E4 acts centrally to control ovulation, we tested its effect on the positive feedback of estradiol (E2) on LH secretion. In ovariectomized females chronically exposed to a low dose of E2, estradiol benzoate (EB) alone or combined with progesterone (P) induced a LH surge and the associated increase in the number of activated kisspeptin (Kp) and gonadotropin-releasing hormone (GnRH) neurons. However, E4 blocked these effects of EB when provided alone, but not when combined to P. These results indicate that E4 blocked the induction of the positive feedback and the associated neuronal activation in the absence of P, suggesting an antagonistic effect of E4 on mERα as shown in peripheral tissues. In parallel, C451A-ERα females do not show a pre-ovulatory LH surge and the associated activation of Kp and GnRH neurons in response to EB unless they are treated with P. The similarity of the responses of C451A-ERα mice and wild-type females treated with E4 supports a role for membrane-initiated estrogen signaling in the EB-induced LH surge.
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