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

Abstract

Functions of tumor suppressor p53 and its negative regulator mouse double minute 2 homolog (Mdm2) in ovarian granulosa cells remain to be elucidated, and the current study aims at clarifying this issue. Mice with Mdm2 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) showed normal fertility, suggesting that p53 induction in the ovarian granulosa cells is detrimental to ovarian function by disturbing oocyte quality. Another model of Mdm2 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 controlled an orphan 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 the Mdm2‐p53‐SF1 axis in ovarian cumulus granulosa cells directs ovarian function by affecting their neighboring oocyte quality.—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. Mdm2‐p53‐SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality. FASEB J. 33, 2610–2620 (2019). http://www.fasebj.org

Characteristics of Circular RNA Expression Profiles of Porcine Granulosa Cells in Healthy and Atretic Antral Follicles

“…Recently, Haraguchi et al (2019) found that in murine ovarian cumulus granulosa cells, the mouse double minute 2 homolog (Mdm2) - steroidogenic factor 1 (SF1) pathway played an important role in oocyte maturation by suppressing p53 activation; deletion of Mdm2 gene expression led to the activation of p53 [ 33 ]. We, however, did not observe differences in the expression of Mdm2 and SF1 in mural granulosa cells of healthy and atretic antral follicles (data not shown).…”

Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion

“…In Pgr ‐Cre female mice, Cre recombinase is expressed not only in the uterus but in the ovary (Soyal et al , 2005). Although Pgr ‐Cre mouse line can be used for deletion of the floxed gene in the entire uterus (Matsumoto et al , 2018), the events regulated by ovarian functions such as ovulation and fertilization need to be evaluated in the pregnant mouse models using Pgr ‐Cre females (Haraguchi et al , 2019). Mice with deletion of Rb1 in the whole uterus ( Rb1 d/d mice) were generated by crossing Pgr ‐Cre with Rb1 ‐floxed mice.…”

Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment

“…Total RNA extraction was performed as described previously 4,6,38,42,43 . The complementary DNA were synthesized from the extracted RNA using ReverTra Ace qPCR RT Master Mix (TOYOBO), and, and qPCR was performed using SYBR Green PCR Master Mix (Thermo Fisher Scientific).…”