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丝裂原活化蛋白激酶对卵母细胞减数分裂成熟和排卵的调控作用及机制

陈露, 江俊超, 戴兴兴, 范衡宇^*

浙江大学生命科学研究院，杭州 310058

摘要

：丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信号通路是一条从酵母到人中都高度保守的信号转导途 径，广泛地存在于各种真核细胞中。近30多年来的研究表明，在几乎所有物种的雌性生殖细胞发育和减数分裂成熟过程 中，该信号通路都发挥着至关重要的作用。特别是在包括人、小鼠和家畜的哺乳动物中，MAPK信号通路在卵母细胞恢复 减数第一次分裂过程中被激活，调控纺锤体组装和细胞周期进程，并在颗粒细胞中介导促性腺激素的生理作用，促进卵丘 扩展、排卵和黄体形成。虽然MAPK信号通路在雌性生殖过程中发挥着如此广泛的生理功能，并且这些功能在进化过程中 高度保守，但是对于其作用机制，特别是其直接作用靶分子，在很长一段时间没有被充分研究清楚。近些年，基于一些新 的基因编辑小鼠模型和理论研究成果，以及各种组学技术的广泛应用，人们进一步揭示了MAPK在减数分裂恢复过程中直 接磷酸化激活RNA结合蛋白——胞质聚腺苷酸化原件结合蛋白1 (cytoplasmic polyadenylation element-binding protein-1, CPEB1)，促进母源mRNA的poly(A)尾延伸，介导蛋白翻译激活。这些研究结果不但构成了目前本领域哺乳动物卵母细胞成 熟和排卵机制的基本理论，也对本领域其他相关研究提供了可借鉴的研究思路。结合本研究组和其他科学家近年来的系统 研究工作，我们对MAPK与卵母细胞成熟和排卵的研究进行了历史回顾，介绍了当前研究进展，提出了新近出现但尚未解 决的科学问题，包括MAPK在颗粒细胞中对mRNA翻译和降解的调控，以及对翻译起始复合体、mRNA加尾酶的直接磷酸化 激活等。

关键词： 丝裂原活化蛋白激酶信号通路; 卵母细胞; 减数分裂成熟; 排卵; 促性腺激素

分类号：Q955;Q492;Q492.5

Function and molecular mechanism of mitogen-activated protein kinase (MAPK) in regulating oocyte meiotic maturation and ovulation

CHEN Lu, Jun-Chao, DAI Xing-Xing, FAN Heng-Yu^*

Life Sciences Institute, Zhejiang University, Hangzhou 310058, China

Abstract

The mitogen-activated protein kinase (MAPK) signaling pathway is a highly conserved signal transduction pathway from yeast to human species, and is widely distributed in various eukaryotic cells. In almost all of the species studied over the past three decades, this signaling pathway plays a crucial role in the development of female germ cells and meiotic maturation. Especially in a variety of mammalian species including primates, rodents, and domestic animals, the MAPK signaling pathway is activated during the resumption of first oocyte meiosis and plays an indispensable role in meiotic spindle assembly and cell cycle progression. In granulosa cells of fully grown ovarian follicles, the MAPK pathway also mediates the physiological action of gonadotropins, including cumulus expansion, ovulation, and corpus luteum formation. Although the MAPK signaling pathway plays a wide range of physiological functions during the female reproduction process, and these functions are highly conserved in evolution, their underlying mechanisms, especially their direct and physiological target molecules, have not been sufficiently studied for a long time. In recent years, based on some new gene-editing mouse models and theoretical findings, as well as the wide application of various omics techniques, it has been further revealed that MAPK directly phosphorylates and activates the RNA binding protein cytoplasmic polyadenylation element-binding protein-1 (CPEB1), promoting poly(A) tail extension of maternal mRNA to regulate protein translation during meiotic recovery. These findings not only constitute the current basic mechanism of mammalian oocyte maturation and ovulation, but also provide useful research ideas for other related research in this field. In this review, we summarize the research findings in our laboratory and from other groups regarding the role of MAPK cascade in regulating oocyte maturation and ovulation. We also discuss the latest research progress on MAPK regulation of mRNA translation and degradation by directly activating the translation initiation complex and mRNA poly(A) polymerase by phosphorylation in the granulosa cells.

Key words: mitogen-activated protein kinase (MAPK) signaling pathway; oocyte; meiotic maturation; ovulation; gonadotropin

收稿日期：2019-06-25　　录用日期：2019-09-22

通讯作者：范衡宇　　E-mail: hyfan@zju.edu.cn

DOI: 10.13294/j.aps.2019.0085

引用本文：

陈露, 江俊超, 戴兴兴, 范衡宇. 丝裂原活化蛋白激酶对卵母细胞减数分裂成熟和排卵的调控作用及机制[J]. 生理学报 2020; 72 (1): 48-62.

CHEN Lu, Jun-Chao, DAI Xing-Xing, FAN Heng-Yu. Function and molecular mechanism of mitogen-activated protein kinase (MAPK) in regulating oocyte meiotic maturation and ovulation. Acta Physiol Sin 2020; 72 (1): 48-62 (in Chinese with English abstract).