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

Cell Death Dis. 2017 Mar 9;8(3):e2662. doi: 10.1038/cddis.2017.82.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Gene Expression Regulation, Developmental
  • Granulosa Cells / metabolism
  • Humans
  • In Vitro Oocyte Maturation Techniques
  • Luteinizing Hormone / genetics
  • Meiosis / genetics*
  • Mice, Knockout
  • Natriuretic Peptide, C-Type / genetics*
  • Oocytes / growth & development
  • Oogenesis / genetics
  • Ovarian Follicle / growth & development
  • Receptors, Atrial Natriuretic Factor / genetics*
  • Receptors, Estradiol / genetics*
  • Receptors, Estrogen / genetics*


  • Receptors, Estradiol
  • Receptors, Estrogen
  • Natriuretic Peptide, C-Type
  • Luteinizing Hormone
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor B