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      Estrogen receptors in granulosa cells govern meiotic resumption of pre-ovulatory oocytes in mammals

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          Abstract

          In mammals, oocytes are arrested at the diplotene stage of meiosis I until the pre-ovulatory luteinizing hormone (LH) surge triggers meiotic resumption through the signals in follicular granulosa cells. In this study, we show that the estradiol (E2)-estrogen receptors (ERs) system in follicular granulosa cells has a dominant role in controlling oocyte meiotic resumption in mammals. We found that the expression of ERs was controlled by gonadotropins under physiological conditions. E2-ERs system was functional in maintaining oocyte meiotic arrest by regulating the expression of natriuretic peptide C and natriuretic peptide receptor 2 (NPPC/NPR2), which was achieved through binding to the promoter regions of Nppc and Npr2 genes directly. In ER knockout mice, meiotic arrest was not sustained by E2 in most cumulus–oocyte complexes in vitro and meiosis resumed precociously in pre-ovulatory follicles in vivo. In human granulosa cells, similar conclusions are reached that ER levels were controlled by gonadotropins and E2-ERs regulated the expression of NPPC/NPR2 levels. In addition, our results revealed that the different regulating patterns of follicle-stimulating hormone and LH on ER levels in vivo versus in vitro determined their distinct actions on oocyte maturation. Taken together, these findings suggest a critical role of E2-ERs system during oocyte meiotic progression and may propose a novel approach for oocyte in vitro maturation treatment in clinical practice.

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          Most cited references48

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          Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene.

          Estrogen receptor and its ligand, estradiol, have long been thought to be essential for survival, fertility, and female sexual differentiation and development. Consistent with this proposed crucial role, no human estrogen receptor gene mutations are known, unlike the androgen receptor, where many loss of function mutations have been found. We have generated mutant mice lacking responsiveness to estradiol by disrupting the estrogen receptor gene by gene targeting. Both male and female animals survive to adulthood with normal gross external phenotypes. Females are infertile; males have a decreased fertility. Females have hypoplastic uteri and hyperemic ovaries with no detectable corpora lutea. In adult wild-type and heterozygous females, 3-day estradiol treatment at 40 micrograms/kg stimulates a 3- to 4-fold increase in uterine wet weight and alters vaginal cornification, but the uteri and vagina do not respond in the animals with the estrogen receptor gene disruption. Prenatal male and female reproductive tract development can therefore occur in the absence of estradiol receptor-mediated responsiveness.
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            Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility.

            Follicle stimulating hormone (FSH) is a member of the glycoprotein hormone family that includes luteinzing hormone (LH), thyroid stimulating hormone, and chorionic gonadotropin. These heterodimeric hormones share a common alpha subunit and differ in their hormone-specific beta subunit. The biological activity is conferred only by the heterodimers. FSH and LH are synthesized in the same cells of the pituitary, the gonadotrophs. FSH receptors are localized to Sertoli cells of the testes and granulosa cells of the ovary. Minimal data has been accumulated so far involving human mutations in the FSH beta, LH beta, or the gonadotropin receptor genes. There are no known mouse strains with mutations in the FSH beta gene. To generate animal models for human diseases involving the gonadotropin signal transduction pathway, we produced mice deficient in the FSH beta subunit and therefore in FSH using ES cell technology. FSH-deficient females are infertile due to a block in folliculogenesis prior to antral follicle formation. Although FSH was predicted to be necessary for spermatogenesis and Sertoli cell growth in males, FSH-deficient males are fertile despite having small testes. Our findings have important implications for male contraceptive development in humans.
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              Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes.

              Granulosa cells of mammalian Graafian follicles maintain oocytes in meiotic arrest, which prevents their precocious maturation. We show that mouse mural granulosa cells, which line the follicle wall, express natriuretic peptide precursor type C (Nppc) messenger RNA (mRNA), whereas cumulus cells surrounding oocytes express mRNA of the NPPC receptor NPR2, a guanylyl cyclase. NPPC increased cGMP levels in cumulus cells and oocytes and inhibited meiotic resumption in vitro. Meiotic arrest was not sustained in most Graafian follicles of Nppc or Npr2 mutant mice, and meiosis resumed precociously. Oocyte-derived paracrine factors promoted cumulus cell expression of Npr2 mRNA. Therefore, the granulosa cell ligand NPPC and its receptor NPR2 in cumulus cells prevent precocious meiotic maturation, which is critical for maturation and ovulation synchrony and for normal female fertility.
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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                March 2017
                09 March 2017
                1 March 2017
                : 8
                : 3
                : e2662
                Affiliations
                [1 ]State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University , No. 2 Yuanmingyuan West Road, Beijing 100193, China
                [2 ]Department of Gynecology and Obstetrics, Medical Center of Reproduction and Genetics, Peking University First Hospital , Beijing 100034, China
                [3 ]College of Biotechnology, Tianjin University of Science and Technology , Tianjin 300457, China
                [4 ]State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing 100101, China
                Author notes
                [* ]State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University , No. 2 Yuanmingyuan West Road, Haidian District, Beijing 100193, China. Tel/Fax: +86 10 62733456; E-mail: glxiachina@ 123456sohu.com
                Article
                cddis201782
                10.1038/cddis.2017.82
                5386574
                28277543
                f4a85d1a-3760-4483-b78f-687b3fd56a58
                Copyright © 2017 The Author(s)

                Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 13 August 2016
                : 27 November 2016
                : 24 January 2017
                Categories
                Original Article

                Cell biology
                Cell biology

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