Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality
Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality
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DOI：
10.1096/fj.201801401r
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发表时间：
2019-02-01
期刊：
影响因子：
4.8
通讯作者：
Osuga, Yutaka
中科院分区：
文献类型：
--
作者：
Haraguchi, Hirofumi;Hirota, Yasushi;Osuga, Yutaka
卵巢颗粒细胞中抑癌基因p53及其负调节基因小鼠双微体2（Mdm 2）的功能尚不清楚，本研究旨在阐明这一问题。卵巢颗粒细胞Mdm 2缺陷小鼠[Mdm 2-loXP/孕激素受体（Pgr）-Cre小鼠]由于卵母细胞成熟、排卵和受精障碍而不育，而颗粒细胞Mdm 2/p53双缺失的小鼠则不育（Mdm 2-loxP/p53-loxP/Pgr-Cre小鼠）显示正常生育力，这表明卵巢颗粒细胞中的p53诱导通过干扰卵母细胞质量而对卵巢功能有害。另一种卵巢颗粒细胞中Mdm 2缺失的模型（Mdm 2-loxP/抗苗勒管激素2型受体-Cre小鼠）也显示出由于排卵和受精失败而导致的生育力低下，表明卵巢Mdm 2在排卵和受精中的关键作用。卵丘颗粒细胞中的Mdm 2-p53通路转录控制孤儿核受体类固醇生成因子1（SF 1），这是卵巢功能的关键调节因子。重要的是，在接受不孕症治疗的患者中，人卵丘颗粒细胞中的MDM 2和SF 1水平与卵母细胞成熟和受精的结果呈正相关。这些发现表明，卵巢卵丘颗粒细胞中的Mdm 2-p53-SF 1轴通过影响邻近卵母细胞的质量来指导卵巢功能。Hirota，Y.，Saito-Fujita，T.，田中，T.，清水广田河Harada，M.，Akaeda，S.，平冈，T.，Matsuo，M.，松本，L.，Hirata，T.，古贺，K.，和田平池岛Fujii，T.，Osuga，Y.卵巢颗粒细胞Mdm 2-p53-SF 1通路通过调节卵母细胞质量指导排卵和受精
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.