Estrogen promotes the development of mouse cumulus cells in coordination with oocyte-derived GDF9 and BMP15

Mol Endocrinol. 2010 Dec;24(12):2303-14. doi: 10.1210/me.2010-0260. Epub 2010 Nov 3.

Abstract

The differentiation and function of cumulus cells depend upon oocyte-derived paracrine factors, but studies on the estrogen receptor knockout mice suggested that estrogen also participates in these processes. This study investigates the possible coordination of estrogen and oocytes in the development and function of cumulus cells using cumulus expansion and the expression of transcripts required for expansion as functional endpoints. Preantral granulosa cell-oocyte complexes developed in vitro with 17β-estradiol (E2) exhibited increased levels of cumulus expansion and Has2 transcripts, encoding hyaluronan synthase 2, compared with those developed without E2. Moreover, cumulus cell-oocyte complexes (COCs) isolated from antral follicles and maintained in culture without E2 exhibited reduced cumulus expansion and Has2 mRNA levels compared with freshly isolated COCs. Exogenous E2, provided during the maintenance culture, alleviated these deficiencies. However, when oocytes were removed from COCs, E2 supplementation did not maintain competence to undergo expansion; the presence in culture of either fully grown oocytes or recombinant growth differentiation factor 9 (GDF9) was required. Recombinant bone morphogenetic protein 15, but not fibroblast growth factor 8, augmented the GDF9 effect. Oocytes or GDF9 suppressed cumulus cell levels of Nrip1 transcripts encoding nuclear receptor-interacting protein 1, a potential inhibitor of estrogen receptor signals. Therefore, E2 and oocyte-derived paracrine factors GDF9 and bone morphogenetic protein 15 coordinate to promote the development of cumulus cells and maintain their competence to undergo expansion. Furthermore, suppression of Nrip1 expression in cumulus cells by oocyte may be one mechanism mediating cross talk between oocyte and E2 signals that promotes follicular development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Bone Morphogenetic Protein 15 / metabolism*
  • C-Reactive Protein / genetics
  • Cell Adhesion Molecules / genetics
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cumulus Cells / cytology
  • Cumulus Cells / drug effects*
  • Cumulus Cells / physiology
  • Cyclooxygenase 2 / genetics
  • Estradiol / pharmacology*
  • Estrogens / physiology
  • Female
  • Fibroblast Growth Factor 8 / metabolism
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • Growth Differentiation Factor 9 / metabolism*
  • Humans
  • Hyaluronan Synthases
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Receptor Interacting Protein 1
  • Oocytes / drug effects*
  • Oocytes / metabolism
  • Receptors, Estrogen / antagonists & inhibitors
  • Receptors, Estrogen / metabolism
  • Signal Transduction / drug effects

Substances

  • Adaptor Proteins, Signal Transducing
  • Bmp15 protein, mouse
  • Bone Morphogenetic Protein 15
  • Cell Adhesion Molecules
  • Estrogens
  • Fgf8 protein, mouse
  • Gdf9 protein, mouse
  • Growth Differentiation Factor 9
  • NRIP1 protein, human
  • Nerve Tissue Proteins
  • Nrip1 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Interacting Protein 1
  • Receptors, Estrogen
  • Tnfaip6 protein, mouse
  • neuronal pentraxin
  • Fibroblast Growth Factor 8
  • Estradiol
  • C-Reactive Protein
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Glucuronosyltransferase
  • Has2 protein, mouse
  • Hyaluronan Synthases