TY - JOUR
T1 - Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality
AU - Haraguchi, Hirofumi
AU - Hirota, Yasushi
AU - Saito-Fujita, Tomoko
AU - Tanaka, Tomoki
AU - Shimizu-Hirota, Ryoko
AU - Harada, Miyuki
AU - Akaeda, Shun
AU - Hiraoka, Takehiro
AU - Matsuo, Mitsunori
AU - Matsumoto, Leona
AU - Hirata, Tetsuya
AU - Koga, Kaori
AU - Wada-Hiraike, Osamu
AU - Fujii, Tomoyuki
AU - Osuga, Yutaka
N1 - Funding Information:
The authors thank Dr. Francesco J. DeMayo (National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA) and Dr. John P. Lydon (Baylor College of Medicine, Houston, TX, USA) for providing Pgr-Cre mice, the National Cancer Institute for providing p53-loxP and Mdm2-loxP mice, Dr. Richard Behringer (The University of Texas MD Anderson Cancer Center, Houston, TX, USA) for providing Amhr2-Cre mice, and Dr. Toshihiro Nakajima (Tokyo Medical University, Tokyo, Japan) for providing a p53-expression plasmid. This work was supported by Precursory Research for Embryonic Science and Technology (PRESTO), Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI; Grants16H04679, 16H05469, 16K15700, 16K15701, 15H04979, 15K10660, 17K16833, 16K10668, 17H06640, 15K15597, 18K19601, 18K19600, 18H02943, and 18K09284), Japan Agency for Medical Research and Development-Precursory Research for Innovative Medical Care (AMED-PRIME; JP17gm5910010), and Takeda Science Foundation. The authors declare no conflicts of interest.
Publisher Copyright:
© 2019 FASEB.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Cell-oocyte complex
KW - Cumulus granulosa
KW - Infertility
KW - Oocyte maturation
UR - http://www.scopus.com/inward/record.url?scp=85061049220&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061049220&partnerID=8YFLogxK
U2 - 10.1096/fj.201801401R
DO - 10.1096/fj.201801401R
M3 - Article
C2 - 30260703
AN - SCOPUS:85061049220
SN - 0892-6638
VL - 33
SP - 2610
EP - 2620
JO - FASEB Journal
JF - FASEB Journal
IS - 2
ER -