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

Hirofumi Haraguchi, Yasushi Hirota, Tomoko Saito-Fujita, Tomoki Tanaka, Ryoko Shimizu-Hirota, Miyuki Harada, Shun Akaeda, Takehiro Hiraoka, Mitsunori Matsuo, Leona Matsumoto, Tetsuya Hirata, Kaori Koga, Osamu Wada-Hiraike, Tomoyuki Fujii, Yutaka Osuga

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Functions of tumor suppressor p53 andits negative regulatormousedoubleminute 2 homolog (Mdm2) in ovarian granulosa cells remain to be elucidated, and the current study aims at clarifying this issue.MicewithMdm2 deficiency in ovarian granulosa cells [Mdm2-loxP/progesterone receptor (Pgr)-Cre mice] were infertile as a result of impairment of oocyte maturation, ovulation, and fertilization, and those with Mdm2/p53 double deletion in granulosa cells (Mdm2-loxP/p53-loxP/Pgr-Cre mice) showednormal fertility, suggesting that p53 inductioninthe ovarian granulosa cells is detrimental to ovarian function by disturbing oocyte quality.Another model ofMdm2 deletion in ovarian granulosa cells (Mdm2-loxP/anti-Mullerian hormone type 2 receptor-Cre mice) also showed subfertility as a result of the failure of ovulation and fertilization, indicating critical roles of ovarian Mdm2 in ovulation and fertilization.Mdm2-p53 pathway in cumulus granulosa cells transcriptionally controlledanorphan nuclear receptor steroidogenic factor 1 (SF1), a key regulator of ovarian function. Importantly, MDM2 and SF1 levels in human cumulus granulosa cells were positively associated with the outcome of oocyte maturation and fertilization in patients undergoing infertility treatment. These findings suggest that theMdm2-p53-SF1 axis in ovarian cumulus granulosa cells directs ovarian function by affecting their neighboring oocyte quality.

Original languageEnglish
Pages (from-to)2610-2620
Number of pages11
JournalFASEB Journal
Volume33
Issue number2
DOIs
Publication statusPublished - 2019 Jan 1

Keywords

  • Cell-oocyte complex
  • Cumulus granulosa
  • Infertility
  • Oocyte maturation

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Haraguchi, H., Hirota, Y., Saito-Fujita, T., Tanaka, T., Shimizu-Hirota, R., Harada, M., Akaeda, S., Hiraoka, T., Matsuo, M., Matsumoto, L., Hirata, T., Koga, K., Wada-Hiraike, O., Fujii, T., & Osuga, Y. (2019). Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality. FASEB Journal, 33(2), 2610-2620. https://doi.org/10.1096/fj.201801401R