Estrogen Receptors Govern Meiotic Progress Of Pre-ovulatory Oocytes In Mammals

Meiosis is a germ cell-specific process. In mammals, it begins during fetal life, but then is arrested at the diplotene stage of meiosis I for prolonged periods. At the same time, the oocytes are enclosed by the surrounding somatic cells and a fixed population of primordial follicles forms. Until the puberty, the arrested oocytes in pre-ovulatory follicles resume meiosis in response to the pre-ovulatory LH surge stimulation. The mature oocytes (eggs) are then available for fertilization within the oviduct. The abnormal meiotic progression, particularly the first meiotic arresting and resumption, may lead to the declined female reproduction rate and infertility. Thus, understanding the mechanisms controlling meiotic progression may contribute to enrich the scientific background behind successful clinical practice in the field of reproductive endocrinology.The meiotic progression is controlled by two pituitary derived gonadotrophins (FSH and LH) during each reproductive cycle. Recently, studies indicate that natriuretic peptide C/natriuretic peptide receptor 2 (NPPC/NPR2) play a critical role in maintaining oocyte meiotic arrest. It is reported that the gonadotrophins could promote meiotic resumption by decreasing NPPC and NPR2; however, how the gonadotropins control NPPC/NPR2 expression and which molecule mediates the signaling network between them are unknown.In this study, we provide evidence showing that the well-known female hormone and its receptors, estradiol and estrogen receptors (E2-ERs), play an indispensable role in the process of oocyte meiosis in mouse and human ovaries. We find that the expression of ERs was controlled by gonadotropins under physiological conditions. Using the CHiP and dual-luciferase assay, we find that E2-ERs system was functional in maintaining oocyte meiotic arrest by directly promoting Nppc/Npr2 gene transcription. In ER knockout (ERKO) mice, E2-promoted Nppc/Npr2 mRNA levels in WT mice were significantly compromised in ERKO mice in vitro and ERKO mice showed a substantial decrease in Nppc/Npr2 mRNA levels in vivo. Moreover, meiotic arrest was not sustained by E2 in most cumulus-oocyte complexes (COCs) in vitro and meiosis resumed precociously in pre-ovulatory follicles in vivo. In human granulosa cells, similar results are reached that gonadotropins controlled the ER levels and E2-ERs regulated the expression of NPPC/NPR2, indicating a potential role for E2-ERs in governing the process of human oocyte maturation. Finally, we show that gonadotropins promoted oocyte meiotic resumption by decreasing ER levels. Interestingly, we find that the different effects of FSH on oocyte maturation in vivo versus in vitro might be result from its opposite regulating patterns toward to ER levels, confirming the significant role of E2-ERs during the process of oocyte maturation.In a word, we have supplied evidences showing that E2-ERs system plays a vital role in governing oocyte maturation by linking gonadotropins and NPPC/NPR2 in mammals.These findings may not only contribute to a more comprehensive understanding of meiotic progression and ovulation but also propose a novel approach for the treatment of oocyte IVM in clinical.