人类卵母细胞减数分裂的生理和病理机制

doi:10.16288/j.yczz.23-170

遗传 ›› 2023, Vol. 45 ›› Issue (12): 1087-1099.doi: 10.16288/j.yczz.23-170

人类卵母细胞减数分裂的生理和病理机制

周舟^1,²(), 桑庆¹(), 王磊¹()

1.复旦大学生物医学研究院，上海 200032
2.上海市生物医药技术研究院，上海 200237

收稿日期:2023-08-07 修回日期:2023-10-11 出版日期:2023-12-20 发布日期:2023-10-24
通讯作者: 桑庆,王磊 E-mail:zhouzhoustudy@163.com;sangqing@fudan.edu.cn;wangleiwanglei@fudan.edu.cn
作者简介:周舟，博士，研究方向：女性生殖遗传学。E-mail: zhouzhoustudy@163.com.
王磊，教授，博士生导师，国家杰出青年科学基金获得者，国家重点研发计划首席科学家(2021)，获科学探索奖(2023)、中国青年科技奖特别奖(2022)、谈家桢生命科学创新奖(2019)等。研究方向为生殖遗传学，重点关注人类卵子、受精及早期胚胎发育的生理与病理机制。以通讯作者在Science、N Eng J Med、Science Transl Med、J Clin Invest、Genome Biol、Am J Hum Genet等发表多篇论文。揭示了人卵母细胞启动纺锤体组装的独特生理机制(Science, 2022)；发现了首个基因突变导致人类卵子成熟障碍并揭示了致病机制(N Eng J Med, 2016)，N Eng J Med杂志同期配发了编者按，认为这是认识卵子成熟障碍机理迈出的第一步；陆续发现了卵子及胚胎发育异常的4种新遗传病，16个致病基因(国际国内已知致病基因为24个)，明确了致病机制并探索了干预策略(J Clin Invest, 2023; Science Transl Med, 2019; Am J Hum Genet, 2016, 2017, 2018, 2020)。所发现的系列新遗传病及致病基因被国际人类孟德尔疾病数据库OMIM收录，相应基因作为分子指标已被国际国内用于临床患者的疾病诊断。主持国家重点研发计划(项目首席)、国家自然科学基金重点项目和面上项目等。
基金资助:
国家自然科学基金项目(82288102);国家自然科学基金项目(32130029);国家自然科学基金项目(81725006);国家自然科学基金项目(82171643);国家自然科学基金项目(81971450);国家重点研发计划(2021YFC2700100);中国博士后科学基金(2022M712147)

Physiological and pathological mechanisms of oocyte meiosis

Zhou Zhou^1,²(), Qing Sang¹(), Lei Wang¹()

1. Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
2. Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China

Received:2023-08-07 Revised:2023-10-11 Published:2023-12-20 Online:2023-10-24
Contact: Qing Sang,Lei Wang E-mail:zhouzhoustudy@163.com;sangqing@fudan.edu.cn;wangleiwanglei@fudan.edu.cn
Supported by:
National Natural Science Foundation of China(82288102);National Natural Science Foundation of China(32130029);National Natural Science Foundation of China(81725006);National Natural Science Foundation of China(82171643);National Natural Science Foundation of China(81971450);National Key Research and Development Program of China(2021YFC2700100);China Postdoctoral Science Fund(2022M712147)

摘要/Abstract

摘要：

正常的卵子发生是人类成功繁育后代的关键步骤。女性胚胎发育时期，原始生殖细胞从有丝分裂转变为减数分裂，经过同源染色体配对和重组后，减数分裂被阻滞在减数第一次分裂前期的双线期。卵泡内卵母细胞的减数分裂阻滞的维持主要归因于胞质中高浓度的环磷酸腺苷。在月经周期中，卵泡刺激素和黄体生成素促进某些卵母细胞恢复减数分裂，完成排卵过程。卵母细胞减数分裂过程中发生任何缺陷都可能影响卵子发生，进而影响受精和胚胎发育过程。辅助生殖、高通量测序和分子生物学技术的快速发展，为人类认识减数分裂背后的精确分子机制以及卵母细胞成熟缺陷疾病的发病机制与诊疗提供新的思路和手段。本文主要介绍了近年来发现的调控卵子发生的生理和病理机制，涉及同源重组、减数分裂阻滞与恢复、母源mRNA降解、翻译后调节、透明带组装等过程，旨在增进相关领域研究人员对卵母细胞减数分裂的了解，并为进一步机制研究和疾病治疗提供理论基础。

关键词: 卵子发生, 卵母细胞, 减数分裂, 突变

Abstract:

Normal oogenesis is crucial to successful reproduction. During the human female fetal stage, primordial germ cells transform from mitosis to meiosis. After synapsis and recombination of homologous chromosomes, meiosis is arrested at the diplotene stage of prophase in meiosis I. The maintenance of oocyte meiotic arrest in the follicle is primarily attributed to high cytoplasmic concentrations of cyclic adenosine monophosphate. During the menstrual cycle, follicle-stimulating hormone and luteinizing hormone lead to the resumption of meiosis that occurs in certain oocytes and complete the ovulation process. Anything that disturbs oocyte meiosis may result in failure of oogenesis and seriously affect both the fertilization and embryonic development. The rapid development of the assisted reproduction technology, high-throughput sequencing technology, and molecular biology technology provide new ideas and means for human to understand molecular mechanism of meiosis and diagnosis and treatment of oocyte maturation defects. In this review, we mainly summarize the recent physiological and pathological mechanisms of oogenesis, involving homologous recombination, meiotic arrest and resumption, maternal mRNA degradation, post-translational regulation, zona pellucida assembly, and so on. We wish to take this opportunity to raise the awareness of researchers in related fields on oocyte meiosis, providing a theoretical basis for further research and disease treatments.

Key words: oogenesis, oocyte, meiosis, variant

周舟, 桑庆, 王磊. 人类卵母细胞减数分裂的生理和病理机制[J]. 遗传, 2023, 45(12): 1087-1099.

Zhou Zhou, Qing Sang, Lei Wang. Physiological and pathological mechanisms of oocyte meiosis[J]. Hereditas(Beijing), 2023, 45(12): 1087-1099.

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致病基因	遗传模式	患者表型	功能	参考文献
TRIP13	AR	卵母细胞MI阻滞、合子分裂失败	调控同源染色体的分离	[29]
REC114	AR	受精后多原核、早期胚胎停滞、反复葡萄胎、流产	调控同源重组的DSBs	[30]
MEI1	AR	早期胚胎停滞、反复葡萄胎、反复流产	调控同源重组的DSBs	[31]
PATL2	AR	卵母细胞GV阻滞、受精失败、早期胚胎停滞	介导翻译抑制途径	[32~34]
PABPC1L	AR	卵母细胞成熟障碍	介导翻译激活途径	[35]
TBPL2	AR	卵母细胞成熟障碍、卵子退化和早期胚胎停滞	介导特定基因的转录	[36]
ZP1	AR	卵子无透明带	组装为卵母细胞透明带	[37]
ZP3	AD	卵子无透明带	组装为卵母细胞透明带	[38]
ZP2	AR	卵子薄透明带、体外受精失败	组装为卵母细胞透明带	[39]
ASTL	AR	受精差和早期胚胎停滞	阻止多精受精	[40]
TUBB8	AD/AR/新发	卵母细胞成熟障碍、受精失败、早期胚胎停滞	构成卵母细胞纺锤体	[41, 42]
FBXO43	AR	早期胚胎停滞	维持卵母细胞MII阻滞	[43]
CDC20	AR	卵母细胞MI阻滞、受精失败、早期胚胎停滞	维持卵母细胞MII阻滞	[44]
MOS	AR	早期胚胎停滞	维持卵母细胞MII阻滞	[45~47]
WEE2	AR	受精失败	抑制MPF的活性	[48]
BTG4	AR	合子分裂失败	介导母源mRNA的降解	[49]
ZFP36L2	AR	早期胚胎停滞	介导母源mRNA的降解	[50]
KPNA7	AR	早期胚胎停滞	介导核转运过程	[51]
CHK1	AD	合子分裂失败	抑制MPF的活性	[52]
TLE6	AR	受精失败或早期胚胎停滞	调控胞质晶格形成	[53]
PADI6	AR	早期胚胎停滞	调控胞质晶格形成	[54]
NLRP2	AR	早期胚胎停滞	调控胞质晶格形成	[55]
NLRP5	AR	受精失败或早期胚胎停滞	调控胞质晶格形成	[55]
KHDC3L	AR	早期胚胎停滞或反复葡萄胎	调控胞质晶格形成	[56]

人类卵母细胞减数分裂的生理和病理机制

Physiological and pathological mechanisms of oocyte meiosis

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