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Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality

Hirofumi Haraguchi1, Yasushi Hirota1,2,3, Tomoko Saito-Fujita1

  • 1Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|September 28, 2018
PubMed

Insights

The Mdm2-p53-SF1 pathway in ovarian granulosa cells is crucial for fertility. Its disruption impairs oocyte maturation, ovulation, and fertilization, highlighting its role in reproductive health.

Area of Science:

  • Reproductive Biology
  • Molecular Endocrinology
  • Cellular Signaling

Background:

  • The roles of tumor suppressor p53 and its regulator mouse double minute 2 homolog (Mdm2) in ovarian granulosa cells are not fully understood.
  • Ovarian granulosa cells are critical for oocyte development, ovulation, and fertilization.

Purpose of the Study:

  • To elucidate the functions of the Mdm2-p53 pathway in ovarian granulosa cells and its impact on female fertility.
  • To investigate the relationship between the Mdm2-p53-SF1 axis and oocyte quality in both mouse models and human infertility patients.

Main Methods:

  • Generation of genetically modified mice with specific deletions of Mdm2 and/or p53 in ovarian granulosa cells using Cre-loxP systems (Pgr-Cre and AMH2R-Cre).
  • Assessment of fertility, oocyte maturation, ovulation, and fertilization rates in these mouse models.
  • Analysis of the Mdm2-p53-SF1 regulatory axis in cumulus granulosa cells and correlation with human oocyte and fertilization outcomes in patients undergoing infertility treatment.

Main Results:

  • Mice with Mdm2 deficiency in granulosa cells exhibited infertility due to impaired oocyte maturation, ovulation, and fertilization.
  • Double deletion of Mdm2 and p53 restored fertility, indicating detrimental effects of p53 induction in granulosa cells on oocyte quality.
  • Mdm2 deficiency in granulosa cells also led to subfertility, with failed ovulation and fertilization, underscoring Mdm2's critical roles.
  • The Mdm2-p53 pathway transcriptionally regulates steroidogenic factor 1 (SF1) in cumulus granulosa cells.
  • Elevated MDM2 and SF1 levels in human cumulus granulosa cells correlated positively with successful oocyte maturation and fertilization in infertile patients.

Conclusions:

  • The Mdm2-p53-SF1 axis in ovarian cumulus granulosa cells is essential for directing ovulation and fertilization by conditioning oocyte quality.
  • Dysregulation of this pathway negatively impacts female reproductive function.
  • Targeting the Mdm2-p53-SF1 pathway may offer therapeutic potential for infertility treatment.
Keywords:
cell-oocyte complexcumulus granulosainfertilityoocyte maturation

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