Glycogen synthase kinase (GSK) 3 in pregnancy and parturition: a systematic review of literature

<b>Introduction:</b> Multiple factors and pathways have been reported as critical machineries for cell differentiation and survival during pregnancy; a number of them involve glycogen synthase kinase (GSK) 3a/β. Several reports on GSK3's functional role exist; however, the specific role of GSK3 in reproductive tissues and its contribution to normal or abnormal parturition are still unclear. To fill this knowledge gap, a systematic review of literature was conducted to better understand the functional role of GSK3 in various intrauterine tissues during implantation, pregnancy, and parturition. <b>Methods:</b> We conducted a systematic review of literature on GSK3's expression and function reported between 1980 and 2017 in reproductive tissues during pregnancy using three electronic databases (Web of Science, Medline, and ClinicalTrials.gov). Study selection, data extraction, quality assessment and analyses were performed in duplicate by two independent reviewers. <b>Results:</b> A total of 738 citations were identified; 80 were selected for full text evaluation and 25 were included for final review. GSK3's regulation and function were mostly studied in tissues and cells from placentas (12), fetuses (8), uteruses (6), and ovaries (2). GSK3 is primarily reported as a downstream responder of protein kinase B (AKT)-, Wnt-, and reactive oxygen species (ROS)-related pathways where it plays a critical role in cell survival and growth in reproductive tissues. <b>Conclusions:</b> Though GSK3 has been functionally linked to a number of biological processes in reproductive tissues, it has primarily been studied as a secondary signaler of various conserved cell signaling pathways. Lack of scientific rigor in studying GSK3's role in reproductive tissues makes this molecule's function still obscure. No studies have reported GSK3 in the cervix, and very few reports exist in myometrium and decidua. This systematic review suggests more functional and mechanistic studies focusing on GSK3 need to be conducted in reproductive biology.

<b>引言：</b>已有多项研究证实，多种因子与通路是妊娠期间细胞分化与存活的关键调控机制，其中诸多通路涉及糖原合酶激酶（glycogen synthase kinase, GSK）3α/β。现有多项研究探讨了GSK3的功能角色，但该激酶在生殖组织中的具体作用，以及其对正常或异常分娩的调控贡献仍未明确。为填补这一研究空白，本研究开展了系统性文献综述，以深入阐明GSK3在着床、妊娠及分娩过程中各类宫内组织内的功能角色。
<b>方法：</b>本研究针对1980年至2017年间发表的、关于妊娠期间生殖组织中GSK3表达与功能的文献开展系统性综述，检索数据库包括Web of Science、Medline及ClinicalTrials.gov。由两名独立研究者分别重复进行文献筛选、数据提取、质量评价及数据分析工作。
<b>结果：</b>本研究共检索到738篇相关文献，其中80篇经全文筛选后纳入评估，最终25篇符合标准进入综述。现有研究多针对胎盘（12项）、胎儿（8项）、子宫（6项）及卵巢（2项）中的组织与细胞，探讨GSK3的调控机制与功能。现有研究普遍认为，GSK3是蛋白激酶B（protein kinase B, AKT）、Wnt及活性氧簇（reactive oxygen species, ROS）相关通路的下游应答分子，在生殖组织的细胞存活与增殖过程中发挥关键调控作用。
<b>结论：</b>尽管GSK3已被证实与生殖组织内的多项生物学过程相关，但现有研究多将其视为各类保守细胞信号通路的次级信号分子。由于现有针对生殖组织中GSK3功能的研究缺乏严谨性，该分子的具体功能仍不明确。目前尚无关于宫颈组织中GSK3的相关研究，针对子宫肌层与蜕膜的报道也极少。本系统性综述提示，未来需在生殖生物学领域开展更多聚焦于GSK3的功能与机制研究。