以早发性卵巢功能不全(premature ovarian insufficiency,POI)为代表的卵巢功能减退性疾病发生的本质是卵巢中卵泡数量的减少或(和)卵泡质量的降低,严重影响女性的生殖健康.卵巢功能减退患者的卵巢中仍然存在部分始基卵泡(primordial follicles,PFs),激活剩余的PFs,使其发育为成熟卵泡,可作为改善卵巢功能的途径之一.PFs是卵泡发育的起点,其休眠和激活的调节是女性维持生育力的重要基础.因此,本文从分子水平探讨PFs激活相关因子及信号通路对卵巢功能的作用机制,重点围绕维持PFs休眠状态的叉头框转录因子O3a(forkhead box O3a,FOXO3a)、叉头框转录因子L2(forkhead box L2,FOXL2)、生殖系α因子(factor in the germline alpha,FIGLA)、LIM同源盒基因 8(LIM homeobox 8,LHX8)、精卵发生特异性HLH转录因子 1/2(spermatogenesis and oogenesis specific basi chelix-loop-helix transcription factor 1/2,SOHLH1/2)、细胞周期蛋白依赖性激酶抑制物 1B(cyclin-dependent kinase inhibitor 1B,CDKN1B)、促进 PFs 激活的新生儿卵巢同源盒蛋白(newborn ovary homeobox gene,NOBOX)、生长分化因子9(growth differentiation factor 9,GDF9)、骨形态发生蛋白15(bone mor-phogenetic protein 15,BMP15)、碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)、白血病抑制因子(leukemia inhibitory factor,LIF),以及参与PFs激活调控的PI3K/AKT/FOXO3a、mTOR、Hippo、TGF-β、AMPK、Notch、cAMP和Wnt等信号通路进行系统性总结和阐述,以期为卵巢功能减退性疾病的预防和治疗提供理论依据及潜在药物靶点.
Research progress on the regulation of primordial follicle activation
Ovarian hypofunction diseases,represented by premature ovarian insufficiency(POI),occurs when the number or/and the quality of the follicles in the ovaries decrease,which seriously affects women's reproductive health.Some primordial follicles(PFs)still exist in the ovaries of patients with hypofunction diseases,and activation of the remaining PFs to mature follicles can be one of the ways to improve ovarian function.PFs are the starting point of follic-ular development,and the regulation of their dormancy and activation is an important basis for the maintenance of fe-male fertility.This article systematically reviews and elucidates the molecular mechanisms underlying the activation of PFs,focusing on key factors such as forkhead box O3a(FOXO3a),forkhead box L2(FOXL2),factor in the germline alpha(FIGLA),LIM homeobox 8(LHX8),spermatogenesis and oogenesis specific basic helix-loop-helix transcrip-tion factors 1/2(SOHLH1/2),cyclin-dependent kinase inhibitor 1B(CDKN1B/p27 Kip1),newborn ovary homeobox gene(NOBOX),growth differentiation factor 9(GDF9),bone morphogenetic protein 15(BMP15),basic fibroblast growth factor(bFGF/FGF2),and leukemia inhibitory factor(LIF).These factors play either a positive or negative role in primordial follicle activation.Additionally,the article discusses various signaling pathways involved in regulating primordial follicle activation,including PI3K/AKT/FOXO3a,mTOR,Hippo,TGF-β,AMPK,Notch,cAMP,and Wnt signaling pathways.This review aims to provide a theoretical foundation and identify potential drug targets for the prevention and treatment of ovarian hypofunction diseases.
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