雌性哺乳动物的繁殖活动是一个高度协调和动态的变化过程。下丘脑、垂体以及生殖系统的共同协作使母体产生具有受精能力的配子来为后续胚胎发育提供支持。关键基因的时空表达调控(转录和转录后的调控)为成功受精和胚胎发育提供了良好的生存环境[1]。长期以来，人们一直认为RNA结合蛋白(RNA-binding proteins, RBPs)参与mRNA转录后调控，并对早期胚胎发育各个阶段的RBPs表达进行了深入研究[2]。然而，随着非编码RNA的发现，尤其是miRNA，为转录后调控提供了一个新的研究方向。
miRNA的生物发生是一个复杂的过程，包括初级miRNA转录、miRNA加工成熟以及功能性miRNA的生成。激活miRNA的第一步是miRNA基因的转录，该基因由RNA聚合酶Ⅱ或RNA聚合酶Ⅲ介导，产生pri-miRNA转录物。此后通过典型途径或非典型途径产生前体miRNA。其中，典型途径主要通过RNase Ⅱ Drosha和DGCR8复合物切割pri-miRNA，并产生长度为60~70个核苷酸的前体miRNA；非典型途径跳过Drosha介导的前体miRNA切割，通过剪接mRNA转录物的内含子而产生前体miRNA[3]。此后，在核转运蛋白5(exportin-5, EXP-5)和GTP辅助因子的作用下前体miRNA向细胞质中转移，进一步被RNase Ⅲ、Dicer复合体与TRBP2共同切割后产生22 nt的双链miRNA，最后与Argonaute(AGO)蛋白相结合，形成miRNA诱导沉默复合体(miRNA-induced silencing complex, miRISC)[4-5]。如图 1所示，miRISC识别靶基因3′-UTR的结合位点导致mRNA降解或蛋白质翻译的抑制[6]。
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图 1 miRNA的发生途径和miRNA生成过程关键基因敲除对雌性哺乳动物繁殖的影响[6] Fig. 1 The pathogenesis of miRNAs and the effects of knocking out key genes involved in miRNA generation on female mammalian reproduction[6] |
近年来，miRNA在雌性动物生殖活动各个方面的作用逐渐被揭开。如图 1所示，研究者们通过构建miRNA成熟过程中关键功能基因(DGCR8、Dicer等)敲除的小鼠模型发现，miRNA在雌性动物的卵泡发育、颗粒细胞增殖和分化、卵母细胞成熟、早期胚胎发育以及相关生殖器官功能中都发挥着重要调节作用[6-11]。迄今为止，大多数被鉴定的miRNAs是细胞内的，但在细胞外环境中也存在许多miRNAs，这类被称为细胞外的miRNA可以与细胞外囊泡、高密度脂蛋白和AGO蛋白偶联，由于其在极端条件下十分稳定，可作为各种生物过程的生物标记[6]。本文主要就miRNA在卵泡发育、卵巢颗粒细胞功能、卵母细胞成熟等雌性哺乳动物繁殖中的功能研究现状进行综述，以期为深入研究miRNA的作用机制，系统全面多层次揭示雌性哺乳动物繁殖活动提供参考。
1 miRNA在卵泡发育的各个阶段发挥调节作用卵泡是卵巢的基本功能单位，各级卵泡(原始卵泡、初级卵泡、次级卵泡、三级/窦状卵泡和成熟卵泡)发育的同时伴随着其内部卵子的成熟过程[12]。卵巢上的各级卵泡众多，理论上每一个卵泡都有发育、排卵潜力，但在正常发情周期中，卵泡发育经过募集、选择和优势化后，仅优势卵泡能破裂并排卵。哺乳动物卵泡发育是一种高度协调和精确调节的生理过程，卵泡的募集、选择、优势化和排卵受到严格的调控[13]。miRNA作为关键的转录后调节RNA分子，在时间依赖性的卵泡发育各阶段(原始卵泡激活、卵泡的募集、选择和优势化)均发挥着重要作用。
1.1 miRNA调控卵巢发育和原始卵泡激活miRNA在人[14]、小鼠[15]、奶牛[16]、山羊[17]、绵羊[18]和猪[19]等哺乳动物卵巢组织中表达。卵巢是卵泡发育的重要场所，2014年，徐源等[20]详述了哺乳动物卵巢miRNA的研究进展，总结了大量miRNAs在卵巢发育、黄体生成、情期转换、卵泡闭锁等生理过程中的参与情况及初步功能。随后的几年，卵巢各个功能细胞(颗粒细胞、卵母细胞等)中miRNA的研究报道越来越多[21-23]，miRNA已成为了哺乳动物卵巢功能研究的重要分子标记，尤其是在人卵巢癌的鉴定和治疗中发挥重要作用[24-25]。另外，多项研究报道了miRNA参与原始卵泡的激活和维持[26-29]。Xu等[26]研究发现，增殖细胞核抗原(proliferating cell nuclear antigen，PCNA)基因是参与卵泡发育的关键基因，在新生小鼠卵巢中利用RNA干扰敲低该基因表达，使得促凋亡基因(BAX、TNF和TNFR-2)表达降低，减少了卵母细胞的凋亡和增加了原始卵泡的发育。此后，Zhang等[27]发现，新生小鼠原始卵泡中miR-376a对PCNA具有转录后调节作用，在培养的小鼠卵巢中过表达miR-376a增加了原始卵泡的数量并减少了卵母细胞凋亡。在新生小鼠卵巢中，miR-145改变了透明带精子结合蛋白基因的表达并激活TGF-β信号通路，进一步证实了miRNA参与促进原始卵泡起始[28]。另有研究发现，miR-143在山羊的前体颗粒细胞中被选择性富集，能够抑制细胞分化和细胞周期相关基因的表达[29]，从而表明，miRNAs对原始卵泡的形成具有显著的抑制效果。此外，研究者在人卵巢癌研究中发现，miRNA-590-3p可以激活卵巢癌细胞的生长和转移，从而抑制原始卵泡的激活[30]。由此可见，miRNA是卵巢原始卵泡发育不可或缺的部分。
1.2 miRNA调控卵泡发育的选择和优势化随着卵泡的增大，包围卵母细胞的颗粒细胞层数量增加，并且由于偏离的发生，卵泡大小的变化十分明显。Sontakke等[31]对牛大小不同卵泡中的miRNA进行了表达分析，并确定了与卵泡选择和优势化的关联。与闭锁卵泡相比，miR-144、miR-202和miR-873在成熟大卵泡中表达上调。为了阐明miRNA在牛发情周期黄体期早期的作用，在发情周期第3(卵泡发育早期)和7天(卵泡发育中期)，Salilew-Wondim等[32-33]分析了牛优势卵泡和非优势卵泡颗粒细胞miRNA的表达特征，发现在发情周期的第3天颗粒细胞miRNA表达并不存在差异，而在第7天颗粒细胞miRNA表达存在显著差异，在mRNA水平也观察到这种现象。最近研究发现，miR-21和3个miRNA簇(miR-183-96-182、miR-132-212和miR-424-450-542)优先富集在牛排卵前优势卵泡的颗粒细胞中，这些miRNA簇可能参与抑制排卵前优势卵泡中颗粒细胞凋亡，从而使优势卵泡排出的过程[34-35]。虽然miRNA在卵泡发育的选择和优势化中可能发挥重要调节作用，但由于该过程比较复杂，对多胎动物而言，很难确定受选择的优势卵泡的个数，因此，目前仅在牛上进行了部分研究，并且大部分结论还未经证实，具体机制还需进一步研究。
1.3 miRNA在卵泡发育过程中的动态变化大多数miRNA表达分析研究的重点是鉴定不同卵泡之间差异表达的miRNAs，但是，研究所有类型卵泡中高表达的miRNAs有助于阐明miRNA在维持卵泡发育的正常生理过程中的调控作用。例如，前期的研究发现，在20种高丰度表达的miRNAs中，15种miRNAs(miR-10b、miR-26a、miR-99b、miR-27b、let-7f、let-7a-5p、let-7i、miR-92a、miR-191、miR-125a、miR-148a、miR-186、miR-143、miR-30d和miR-30a-5p)的表达与卵泡类别无关[32, 36]。并且这些miRNAs在奶牛[16]、山羊[37]、猪[38]和其它哺乳动物[39-41]卵巢组织中普遍表达。表明这些miRNAs在维持雌性哺乳动物繁殖正常生理过程中起“管家”作用。
发情周期内卵泡生长、卵丘偏离以及卵泡闭锁的分子机制可以通过研究颗粒细胞基因表达的动态变化来进行判断[42-43]。因此，在发情周期的不同时间点鉴定哺乳动物颗粒细胞中miRNA的表达趋势能为卵泡发育的转录后基因调控机制增加新的见解。为此，以牛为例，研究者对发情周期中第3和7天差异表达的miRNAs进行了mate分析，对卵泡发育时间和卵泡类型的最小二乘平均值以及第3和7天、第7和19天的线性回归进行计算发现，miR-132-212和miR-183-96-182簇可能通过在发情周期的后期促进优势卵泡中颗粒细胞存活来影响排卵活动[35, 44]。另外还发现，优势卵泡中miRNA簇(miR-23a-27a-24、miR-222-221和miR-214-199a)在第3~7天表达增加，直到发情周期的卵泡期，在颗粒细胞的表达才减少。之后，研究者发现，miR-23a和miR-27a通过靶向SMAD5促进颗粒细胞凋亡[45]。综上所述，在哺乳动物发情周期的整个过程中，“管家miRNA”表达的动态变化对卵泡的发育起重要调控作用，部分简单的调控示意图见图 2。
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图 2 发情周期优势卵泡颗粒细胞miRNA动态表达情况[35, 44-45] Fig. 2 miRNA expression dynamics in granulosa cells of dominant follicles during the estrous cycle[35, 44-45] |
颗粒细胞的增殖、分化和类固醇生成对于哺乳动物整个卵泡发育是必不可少的，其调控包括卵泡的募集、选择和优势化以及卵泡的选择性闭锁多个生物学过程。由于颗粒细胞在体外相对容易分离培养，是卵巢功能研究的主要细胞类型。前期研究通过在颗粒细胞中特异性缺失Dicer证明了其在哺乳动物卵泡发育中的重要作用[11]。一些分子遗传学研究者以颗粒细胞作为模型，用大量体外敲除或过表达研究发现，miRNA在颗粒细胞增殖、分化和类固醇生成中也发挥重要作用。表 1总结了部分已经验证的miRNAs在不同细胞类型中的作用。
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表 1 miRNAs在不同哺乳动物生殖细胞中的作用 Table 1 The role of miRNAs in different reproductive cells of different mammalian |
颗粒细胞的增殖为卵母细胞生长创造了一个独特的微环境。前人已经证实TGF-β超家族成员在颗粒细胞增殖中发挥重要作用。Yao等[70]最早发现，miR-224通过靶向Smad4增强TGF-β介导的小鼠颗粒细胞增殖。随后研究发现，miR-10家族成员通过抑制TGF-β通路中的关键基因(TGFβ1、BMP4和BMP15)，减缓颗粒细胞增殖速度，并诱导人、小鼠和大鼠颗粒细胞凋亡，表明miRNA和TGF-β途径之间存在负反馈调节作用，在颗粒细胞增殖或凋亡中发挥重要作用[40, 63]。近期，Pande等[73]通过miRNA的过表达和敲除等方法发现miR-424/503簇成员通过靶向激活素信号通路中的SMAD7和ACVR2A基因来调节牛颗粒细胞增殖和细胞周期进程，暗示miR-424/503簇成员可能是牛颗粒细胞增殖和分化的关键因子。此外，在体外培养的人颗粒细胞中添加miR-15a的反义互补序列发现，颗粒细胞增殖相关标记基因(MAPK/ERK1和PCNA)表达显著上升，而过表达miR-15a后这些标记基因的表达显著降低[90]。表明miR-15a可能是调节颗粒细胞增殖或凋亡的又一关键调节因子。
众所周知，在卵泡发育期间招募的大多数卵泡发生闭锁是由颗粒细胞凋亡引起的，越来越多的证据表明，miRNA在调节颗粒细胞凋亡和确定优势卵泡中发挥作用。在LH达到诱导排卵的浓度时，miR-21在小鼠的卵巢颗粒细胞中显著富集，当miR-21被抑制后，小鼠的排卵率降低[90]。在牦牛中，研究者发现，miRNA-125b首先靶向结合BMPR1B基因，进而影响其mRNA和蛋白的表达以及凋亡因子Bcl2/Bax的比例，最终在颗粒细胞中促进和抑制细胞凋亡[64]。近期，在类似的研究中还发现，miR-99a可以通过靶向IGF-1R调节人的颗粒细胞凋亡[65]。另一项研究发现，miR-92a通过靶向SMAD7基因调节其表达来防止TGF-β诱导的颗粒细胞凋亡[91]，与miR-21的作用机制基本一致。
排卵前优势卵泡颗粒细胞中miR-183-96-182簇的富集与促凋亡基因FASL的下调有关，而FASL已被证实是促进颗粒细胞凋亡的关键因子，因此miR-183-96-182簇可能参与颗粒细胞的凋亡调控[34]。miR-22的作用机制与miR-183-96-182簇基本一致，但主要是调节Bax和其它一些促凋亡基因的表达[92]。
为了确定miRNA对卵巢细胞类固醇生成的影响，研究者将80种人的miRNAs前体结构转染到体外培养的颗粒细胞中进行全基因组筛选试验。发现其中10种miRNAs促进颗粒细胞释放黄体酮，36种miRNAs可抑制黄体酮释放。同时，雌二醇的释放也受到51种miRNAs的抑制[93]。在培养的小鼠颗粒细胞中过表达miR-378可下调孕酮受体基因(PR)及其下游转录本的转录[50]；同时，miR-378还可以抑制芳香酶蛋白的表达从而抑制猪颗粒细胞产生雌二醇[76]。在猪和小鼠颗粒细胞中，miR-34a和miR-320过表达也具有抑制颗粒细胞产生雌二醇的作用[62, 94]。miRNA不仅参与调节哺乳动物的类固醇激素合成，而且它们的表达也受到卵泡环境中类固醇激素水平和组成的影响[95]。当母牛的血液循环中FSH浓度升高可引起卵泡液和血浆循环, miRNA表达发生改变，这可能与卵母细胞发育有关[96]。
3 卵母细胞成熟过程中miRNA的表达及作用卵母细胞成熟是通过有序的减数分裂、染色质重塑和细胞质细胞器重组等在形态学、生理学方面发生变化的过程。卵母细胞成熟过程中，母体的mRNA和蛋白质对早期胚胎卵裂和发育至关重要[97]。全基因表达研究发现，约400个基因在未成熟和成熟的猪卵母细胞中差异表达[98]，在牛卵母细胞成熟过程中多达821个基因被差异调控[99]。因此，了解蛋白质和mRNA在卵母细胞成熟的不同阶段中显著积累或降解的机制是雌性配子发生领域的研究重点。
在哺乳动物中，已知3种主要类型的小RNA(miRNA、siRNA和PIWI互作RNA)通过与AGO蛋白的相互作用在转录后调节基因表达。对人、牛、猪生长阶段和成熟后卵母细胞miRNA组研究发现，miRNA生物学表达模式存在差异[6, 76, 100-102]。例如，miR-21通过其靶基因可能参与卵母细胞成熟过程中脂肪酸代谢和脂肪酸生物合成[58]，增加卵丘细胞中miR-224的表达可通过PTX3表达变化降低卵母细胞成熟率和胚胎发育[70]。在牛卵母细胞体外成熟过程中，降低miR-130b的活性可以抑制第一极体的排出[77]，以上研究表明，miRNA在卵母细胞生长和成熟过程中发挥重要作用。
在体外条件下，miRNA组的动态变化主要取决于培养条件，而在体内，miRNA组的变化可能受生理条件如动物年龄的影响。例如，用胰岛素样生长因子1(insulin-like growth factor 1，IGF1)处理人卵母细胞可激活miR-133a、miR-205-5p和145种miRNAs的表达，并抑制其它200种miRNAs表达[103]；另一方面，与年轻女性相比，老年女性的卵母细胞中12种miRNAs的表达改变，暗示卵母细胞中的miRNA组受卵母细胞老化的影响[104]。然而，这些随年龄变化miRNAs的作用机理还有待进一步研究。
4 细胞外囊泡中miRNA参与哺乳动物卵泡发育细胞外小泡是细胞间信息传递的重要介质，并且调节多种生物学过程。基于它们的细胞来源，细胞外小泡分为外泌体、微粒、前列腺体、远端小体和心肌小体。根据它们的生物发生和大小，细胞外囊泡可以分为外泌体(30~130 nm)、微泡(50~1 000 nm)和凋亡体(500~2 000 nm)。有证据表明，外泌体介导的细胞间信息交流对于疾病的判断十分重要[105-106]。例如，外泌体携带的蛋白质可用作癌症诊断的工具[106]。在绵羊中，细胞外囊泡已被证明在母体和胚胎间的联系中起重要作用。各类细胞对细胞外囊泡摄取过程中，囊泡将其遗传物质(mRNA，miRNA等)转移到受体细胞，导致内源miRNA水平的增加[107]。为了探究囊泡的作用机制，研究者从直径3~6 mm的牛卵泡液中分离出细胞外囊泡补充到体外培养的成熟卵母细胞和早期胚胎中，发现mRNA、miRNA、DNA甲基化和羟甲基化模式均有显著变化。并且在补充来自小卵泡的细胞外囊泡时，卵丘扩张和标记基因的表达十分显著[108]。
根据ExoCarta在线外泌体数据库(http://exocarta.org)提供的信息，在外泌体中存在大量蛋白质、mRNA、miRNA和数百种脂质。在过去5年中，针对外泌体及其内容物的研究急剧增加。在各种生物体液中发现，外泌体中包含大量miRNAs，并且这些miRNAs在雌性繁殖相关细胞间的信息传递中发挥重要作用[109-111]。表 1总结了部分大鼠、小鼠、人和牛卵泡液中具有调节作用的miRNAs。这些细胞外环境中的miRNAs非常稳定，可承受极端条件(例如频繁的冷冻和解冻)，研究者预测，这些miRNAs可以作为卵母细胞和胚胎发育能力的潜在生物标志物。
5 小结与展望从原始卵泡激活到卵母细胞成熟的整个过程中，miRNA在雌性哺乳动物中均发挥着重要作用。除了它们的组织特异性表达和作用外，也有大量的miRNAs被释放到细胞外环境中作为细胞间通信的关键分子促进细胞间信息交流。虽然在过去的十几年间miRNA的表达及功能研究如火如荼，但miRNA和mRNA之间存在的一对多和多对一的复杂互作调控关系为miRNA的作用机理研究增加了困难。到目前为止，仅确定了很少一部分miRNAs在雌性哺乳动物繁殖中的作用机理。前人的研究已经证明，miRNA在雌性哺乳动物的繁殖过程中作用巨大，并且由于miRNA的序列很短，结构相对稳定，未来很有可能成为判断雌性哺乳动物繁殖能力的分子标记。
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