猪Gpr3基因特征、表达及其对卵泡颗粒细胞的影响
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摘要
哺乳动物卵泡发育是一个复杂的生理生化过程,主要包括：原始卵泡的募集、腔前卵泡的发育、有腔卵泡的选择和生长及卵泡的成熟或闭锁。该过程受激素、生长因子、金属离子等多种因素控制,最终只有少数卵泡发育为优势卵泡并排卵,99%以上的卵泡发生闭锁。卵泡颗粒细胞是卵泡中最重要的体细胞,它对卵母细胞成熟、卵泡发育有至关重要的作用。伴随着哺乳动物卵泡生长和发育,颗粒细胞体积增大、数量增多并逐步分化和成熟。G蛋白偶联受体3(G protein-coupled receptor3, Gpr3)属于G蛋白偶联受体超家族成员。近年来的研究表明,Gpr3在小鼠和人的卵巢中通过Gs蛋白介导的下游通路调节卵泡的生长发育和卵母细胞的成熟。但Gpr3在猪卵巢中的表达规律及在卵泡颗粒细胞中的作用目前尚未见报道。因此,深入研究猪Gpr3在卵巢及卵泡发育过程中的表达规律,探索Gpr3信号通路在卵泡颗粒细胞中的作用及其调控机制,可以为哺乳动物繁殖性状的选育提供可能的理论基础,在提高家畜繁殖性能方面具有重要意义。
本论文以三元商品猪为研究对象,采用电子克隆与传统克隆相结合的方法,利用RT-PCR和RACE技术,获得了猪Gpr3基因的全长序列和含有完整编码框的Gpr6及Gprl2的部分cDNA序列,并利用生物信息学方法对其结构及功能进行了系统的研究；利用实时荧光定量(real-time) PCR和免疫蛋白印迹(Western blotting)技术对Gpr3在组织及卵母细胞体外成熟过程中的表达规律进行了分析；利用免疫组织化学方法对猪胎儿期50、70和90(日龄)、新生1日龄及生后期25、35、70、140和180(日龄)9个阶段猪卵巢组织中Gpr3蛋白的表达进行了细胞定位；利用real-time PCR和Western blotting技术对不同日龄、不同品种卵巢及不同直径卵泡中Gpr3的表达规律进行了分析；利用构建的Gpr3真核表达载体及与GFP融合表达载体检测了Gpr3在人胚肾(HEK293)细胞中的亚细胞定位、组成性活性以及鞘脂类脂质对Gpr3组成性活性和受体内化作用的影响；采用RNAi技术敲减Gpr3,阻抑Gpr3介导的信号通路,利用MTT、流式细胞术、放射免疫测定(Radioimmunoassay, RIA)、real-time PCR等方法检测阻抑该信号通路对猪卵泡颗粒细胞的作用及其分子机制；采用超表达Gpr3的方式激活其介导的信号通路,利用MTT、流式细胞术、RIA、real-time PCR等方法检测超表达Gpr3后对猪卵泡颗粒细胞生长及分化的影响,主要研究结果如下：
1用电子克隆和RACE的方法克隆了猪Gpr3基因的全长序列和含有完整编码框的Gpr6及Gpr12的部分cDNA序列,GenBank登录号分别为HQ606483、HM777010和HM77711,并做生物信息学预测分析,结果表明：猪Gpr3基因的cDNA由2101个核苷酸组成,编码330个氨基酸,分子量为35.2kDa,位于第6号染色体,与牛、犬、人、黑猩猩、小鼠和大鼠的氨基酸相似性分别为96.4%,95.1%,94.9%,94.8%,90.0%和85.4%。它具有典型的七次跨膜结构域,存在多个潜在的磷酸化和糖基化修饰位点,表明它是一个功能活跃的跨膜蛋白,可能参与信号传导、细胞生长调控等过程。另外,猪Gpr3、Gpr6和Gpr12的蛋白序列比对及功能预测分析发现,它们彼此间具有高度的序列同源性和相似的潜在功能,将三者归为同一受体亚家族,称为Gpr3亚家族。
2用real-time PCR和Western blotting的方法检测猪Gpr3基因的组织分布及在卵母细胞成熟过程中的表达模式,结果表明：猪Gpr3基因在大脑、小脑、下丘脑、垂体、心脏、肝脏、脾脏、肺脏、’肾脏、肌肉、脂肪、胸腺、卵巢、输卵管、子宫、睾丸、卵母细胞和颗粒细胞中均有表达,但仅在脑、垂体、肝脏、脂肪、子宫和卵母细胞中大量表达,推测其在猪的神经系统及生殖系统发育和功能维持方面具有重要作用,可能参与猪的脂肪代谢。另外,Gpr3基因在猪卵母细胞体外成熟过程中的表达量呈下降趋势,并且与卵丘扩散程度呈显著的负相关(r=-0.937,P<0.01),表明其可能对卵丘扩散和卵母细胞成熟具有重要作用。成熟促进因子(Maturation promoting factor, MPF)的调节亚基Cyclin B1基因在卵母细胞体外成熟前期的表达量较低(0-24h),后期显著的升高(24-44h),而催化亚基CDK1基因的表达水平在整个培养过程中保持相对稳定,说明MPF可能主要在卵母细胞体外成熟后期发挥作用。
3用免疫组织化学方法检测Gpr3蛋白在9个阶段猪卵巢组织中的表达与定位,结果表明：在胎儿和新生期,Gpr3主要在卵母细胞巢中的卵原细胞、原始卵泡和初级卵泡的卵母细胞中表达；在生后期,Gpr3在腔前卵泡和有腔卵泡的颗粒细胞层、卵丘细胞和卵母细胞胞质中表达,并且在卵母细胞中的表达量最高。另外,在成年猪卵巢的黄体中也有微弱的表达。Real-time PCR和Western blotting结果表明,Gpr3mRNA和蛋白在不同发育阶段猪卵巢中均有表达,表达量呈波浪状变化,在新生及出生后140日龄的表达量最高；在不同品种猪的卵巢中,Gpr3的表达量趋于一致,未见显著性差异；在不同直径猪卵巢卵泡中,Gpr3的表达量随着卵泡直径的增加而上升。猪Gpr3受体在卵巢中的细胞和时期特异性表达模式表明,其可能在猪卵泡发育和黄体形成过程中发挥重要作用。
4为了探究Gpr3的性质功能并筛选其潜在的配体,我们构建了Gpr3真核表达载体及与GFP融合表达载体,用以检测Gpr3在人胚肾(HEK293)细胞中的亚细胞定位、组成性活性、鞘脂类脂质对组成性活性和受体内化的影响。结果表明：在HEK293细胞中,Gpr3的表达引起了腺苷酸环化酶(adenylate cyclase, AC)组成性激活,并且激活程度与完全激活Gs偶联受体的程度相似。而且,鞘氨醇1-磷酸(sphingosine1-phosphate, S1P)可以通过组成性激活的Gpr3受体进一步增加AC的活性。当在HEK239细胞中表达绿色荧光蛋白(green fluorescent protein, GFP)标记的Gpr3受体时发现,绿色荧光仅集中于细胞膜和亚细胞膜中。S1P处理后,通过荧光共聚焦显微镜可以观察到激动剂诱导的受体内化过程。而鞘氨醇(sphingosine, Sph)和鞘磷脂(sphingomyelin, Sphi)不具备以上功能。说明,Gpr3是组成性激活的G蛋白偶联受体,它的组成性活性及激动剂诱导的内化作用受到脂质调节者S1P的调控,表明S1P可能是猪Gpr3受体的潜在激动剂。
5为了研究Gpr3信号通路在猪卵泡颗粒细胞中的作用,本研究从猪卵巢卵泡(3-5mm)内分离颗粒细胞(pGCs)进行体外培养。采用RNAi技术“沉默”Gpr3阻抑其介导的信号通路,以检测Gpr3受体在猪卵泡颗粒细胞生长及分化过程中的作用。结果表明：转染Gpr3特异性的siRNA后,能够有效地抑制颗粒细胞中Gpr3mRNA和蛋白的表达,成功地阻抑了Gpr3介导的信号通路。MTT、流式细胞术及RIA检测的结果表明,阻抑Gpr3信号通路能够促进颗粒细胞增殖,抑制颗粒细胞凋亡,但对颗粒细胞中类固醇激素的合成没有影响。另外,阻抑Gpr3信号通路显著改变了Cyclin B1、 Cyclin D2、Bcl-2、Bax和Gprl2的表达(P<0.05),而对CDK1、CDK4、P450arom、 P450scc和Gpr6的表达没有影响(P>0.05)。
6为了进一步明确Gpr3在猪颗粒细胞中的功能,我们在颗粒细胞中超表达了Gpr3受体,结果表明：超表达Gpr3能显著抑制颗粒细胞的增殖,增加G0/G1期细胞的百分含量,减少S期的细胞,同时降低细胞周期标志蛋白Cyclin B1和CDK1的mRNA表达；超表达Gpr3能显著增加颗粒细胞的凋亡比率,抑制Bcl-2的表达,促进Bax的表达；超表达Gpr3促进了Gpr6的表达；然而,超表达Gpr3不影响雌二醇和孕酮的分泌,并且未显著改变P450arom和P450scc的表达。由此可见,Gpr3信号通路在调控猪卵泡颗粒细胞生长和凋亡过程中具有重要的作用,相关基因表达量的改变为进一步探索Gpr3受体在调节卵泡颗粒细胞生长及凋亡过程的中作用机制奠定了一定的基础。
Mammalian follicular development is a very complex physiological and biochemical cascade process, including recruitment of the primitive follicle, the development of preantral follicle and antral follicle selection, growth and mature or follicle atresia. This procedure can be regulated by a lot of factors, such as hormones and growth factors. It is well known that only a few follicles can reach dominant follicles and ovulation, and more than99%follicles go atresia in mammals. Granulosa cells are key somatic cells in follicles, and play very important roles in oocyte maturation and follicular development. Follicular development is accompanied by growth, proliferation, differentiation, and maturation of granulosa cells. G protein-coupled receptor3(Gpr3) belongs to the G protein-coupled receptor superfamily. Recent study showed that Gpr3regulated follicular development and oocyte maturation through Gs-linked signal pathways in ovarian cells of mice and human. However, the expression pattern in ovary and the roles in follicular granulosa cells of Gpr3are have not yet been well documented in pigs. Therefore, it is immediately required to carry out the further study on the expression pattern of Gpr3and regulatory mechanisms of the Gpr3signaling pathway in the follicular granulosa cells of pigs, which provides possible rationale to selection of mammalian reproductive trait and has great importance to the improvement of reproductive capacity of domestic animals.
In this study, using in silico approach combined with reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE), we cloned the full-length of porcine Gpr3gene and the complete coding sequences of porcine Gpr6and Gpr12genes. Bioinformatics methods were adopted to predict the structure and function of Gpr3, Gpr6and Gpr12protein. Real-time RT-PCR and Western blotting were performed to investigate Gpr3expression pattern in tissues and the whole cumulus-oocyte complexes (COCs) of in vitro maturation (IVM). Cellular localization of Gpr3in the ovaries of50,70and90post coitum (dpc), days1,25,35,70,140and180postpartum (dpp) of commercial pigs were examined by immunohistochemistry (IHC). Time-spatial expression of Gpr3in multi-age, multi-breed ovaries and multi-diameter follicles were detected by Real-time RT-PCR and Western blotting. Subcellular localization, constitutive activity of Gpr3and the effect of sphingolipids on its constitutive activity and ligand-induced receptor internalization were tested using the vectors of pcDNA-Gpr3and pEGFP-Gpr3in HEK293cells. In order to repress Gpr3signaling, the gene of Gpr3was silenced by RNAi, the effects of repressed Gpr3signaling on porcine follicular granulosa cells and underlying molecular mechanism were detected by MTT, FCM, RIA and real-time RT-PCR. The effects of Gpr3overexpression on porcine follicular granulosa cells and underlying molecular mechanism were also detected by MTT, FCM, RIA and real-time RT-PCR.
The main results achieved were as follows:
1The full-length of porcine Gpr3gene and the complete coding sequences of porcine Gpr6and Gprl2genes were cloned by RT-PCR and RACE, and were submitted to GenBank (Accession No. HQ606483, HM777010and HM77711, respectively). Using bioinformatics network resources and relevant software, we predicted that the full sequence of Gpr3gene with its length being2101bp nucleotides, including an open reading frame of993bp, encoded a330amino acid polypeptide with the molecular weight of35.2kDa, localizeg at chromosome6. Comparison of the putative amino acid of porcine orthologs with that of other species showed that porcine Gpr3shared96.4%,95.1%,94.9%,94.8%,90.0%and85.4%homology with Bos taurus (XP612644.2), Canis lupus familiaris (XP544470.1), Homo sapiens (NP005272.1), Pan troglodytes (XP001148989.1), Mus musculus (NP032180.1) and Rattus norvegicus (NP714949.1) respectively, which proved that Gpr3gene was well conserved in the process of evolution. The Gpr3protein contained the typical seven-transmembrane structure of G protein-coupled receptors (GPCRs), including several potential phosphorylation and N-glycosylation sites, suggesting that it might be involved in signal transduction and regulation of cell growth process. Further, on the basis of their high levels of sequence similarity and similar potential roles, Gpr3, Gpr6and Gpr12genes were identified as a subfamily of GPCRs, called Gpr3subfamily of GPCRs.
2Expression patterns of Gpr3in tissues and the whole COCs during IVM were investigated by real-time RT-PCR and Western blotting. The results indicated that Gpr3gene was expressed in tissues of cerebrum, cerebellum, hypothalamus, pituitary, heart, liver, spleen, lung, kidney, muscle, fat, thymus, ovary, oviduct, uterus, testis, oocyte, and granulosa cell at different expression levels, the expression levels of this gene in brain, pituitary, liver, fat, uterus and oocyte being higher than that in other tissues. Since Gpr3mRNA and protein were detected in porcine hypothalamus-pituitary-ovary and testis, it can be speculated that this receptor may play an important role in the neural regulation of sexual and/or reproductive functions and fat metabolism in pigs. Interestingly, the mRNA and protein levels of Gpr3in the whole COCs were down-regulated, and its mRNA expression levels were significantly and negatively correlated with the degrees of cumulus expansion (r=-0.937, P<0.01) during IVM, suggesting its important roles in cumulus expansion and oocyte maturation. Maturation/M-phase promoting factor (MPF) is a complex composed of a regulatory subunit cyclin B1and a catalytic subunit CDK1. Cyclin B1transcripts was up-regulated after24h of maturation, while CDK1mRNA levels were unchanged during IVM, suggesting that MPF might play roles in the later stage of oocyte maturation.
3Cellular localization and expression pattern of Gpr3were investigated by IHC, real-time PCR and Western blotting in the ovaries of pigs. The results showed that Gpr3protein was primarily expressed in the oogonia in egg nest and the oocyte in primodial and primary follicles of the fetal and neonatal pigs. In postnatal pigs, Gpr3protein was expressed mainly in the granulosa cell layer, cumulus cell and cytoplasm of oocytes. Furthermore, the immunostaining for Gpr3in cytoplasm of oocytes was the most intensive. In additional, the staining intensity was faintly presented in the corpora lutea of the ovary in adult pigs. The results of real-time PCR and Western blotting indicated that Gpr3mRNA and protein were both presented in the different ages of ovaries, and the expression levels were wave-changed from postpartum1to180days. The expression levels of Gpr3in the1-dpp-old and140-dpp-old ovaries were higher than that of other age ovaries. There was no significant difference among three tested breeds at the expression level of Gpr3in the ovary. Moreover, both mRNA and protein levels of Gpr3were up-regulated significantly during follicle growth. The stage-and cell-specific expression pattern of Gpr3in the porcine ovary suggested that Gpr3might play an important role in the process of entire follicular development and luteinization.
4In order to understand the properties and functions of Gpr3, by which to screen its potential ligands, the vectors of pcDNA-Gpr3and pEGFP-Gpr3were constructed for checking the subcellular localization, constitutive activity of Gpr3and the effect of sphingolipids on its constitutive activity and ligand-induced receptor internalization in HEK293cells. The results showed that expression of porcine Gpr3in HEK293cells resulted in constitutive activation of adenylate cyclase (AC) similar in amplitude to that produced by fully stimulated Gs-coupled receptors. Moreover, sphingosine1-phosphate (SIP) could increase AC activation via the constitutively active Gpr3receptor. When expressed in HEK293cells, GFP-labeled Gpr3protein was shown to be localized in the plasmalemma and subcellular membranes. After SIP treatment, agonist-mediated intemalization could be visualized by confocal microscopy. However, sphingosine (Sph) and sphingomyelin (Sphi) had no ability like that of S1P. In short, our findings suggested that the porcine Gpr3is a constitutively active G protein-coupled receptor. Constitutive activation of AC and agonist-mediated intemalization of Gpr3receptor could be modulated by the SIP, suggesting that SIP might act as an activator for porcine Gpr3receptor.
5To demonstrate the effects of Gpr3signaling pathways on growth and differentiation of porcine granulosa cells (pGCs), pGCs were isolated from3-5mm antral follicles in diameter and cultured in vitro. A strategy of RNAi-mediated gene silencing of Gpr3was used to repress endogenous Gpr3signaling in cells. The results indicated that GprJ-siRNA causes specific inhibition of Gpr3mRNA and protein expression after transfection, which successfully repressed endogenous Gpr3signaling in pGCs. Repressed endogenous Gpr3signaling significantly promoted growth and inhibited apoptosis of pGCs, but no effect was shown on steroidogenesis in pGCs. In addition, repressed Gpr3signaling significantly changed the mRNA expression of Cyclin B1, Cyclin D2, Bcl-2, Bax and Gpr12(P<0.05), but there is no change in the expression of CDK1, CDK4, P450arom, P450scc and Gpr6(P>0.05).
6To further confirm the roles of Gpr3in pGCs, Gpr3overexpression was performed in pGCs. The results showed that Gpr3overexpression significantly inhibited porcine GCs proliferation, increased the proportion of G0/G1-phase cells, and decreased the cells of S-phase and the mRNA expression of Cyclin B1and CDK1; Gpr3overexpression significantly induced apoptosis of porcine GCs, decreased the expression of Bcl-2, and increased the expression of Bax; Gpr3overexpression significantly increased the expression of Gpr6. However, there was no effect of Gpr3overexpression on steroidogenesis and related genes in pGCs. These results implied that Gpr3signaling play an important role in pGCs, and the change of genes related to cell growth and apoptosis were provided a basis for further research on the regulatory mechanisms of porcine Gpr3gene in pGCs.
本论文以三元商品猪为研究对象,采用电子克隆与传统克隆相结合的方法,利用RT-PCR和RACE技术,获得了猪Gpr3基因的全长序列和含有完整编码框的Gpr6及Gprl2的部分cDNA序列,并利用生物信息学方法对其结构及功能进行了系统的研究；利用实时荧光定量(real-time) PCR和免疫蛋白印迹(Western blotting)技术对Gpr3在组织及卵母细胞体外成熟过程中的表达规律进行了分析；利用免疫组织化学方法对猪胎儿期50、70和90(日龄)、新生1日龄及生后期25、35、70、140和180(日龄)9个阶段猪卵巢组织中Gpr3蛋白的表达进行了细胞定位；利用real-time PCR和Western blotting技术对不同日龄、不同品种卵巢及不同直径卵泡中Gpr3的表达规律进行了分析；利用构建的Gpr3真核表达载体及与GFP融合表达载体检测了Gpr3在人胚肾(HEK293)细胞中的亚细胞定位、组成性活性以及鞘脂类脂质对Gpr3组成性活性和受体内化作用的影响；采用RNAi技术敲减Gpr3,阻抑Gpr3介导的信号通路,利用MTT、流式细胞术、放射免疫测定(Radioimmunoassay, RIA)、real-time PCR等方法检测阻抑该信号通路对猪卵泡颗粒细胞的作用及其分子机制；采用超表达Gpr3的方式激活其介导的信号通路,利用MTT、流式细胞术、RIA、real-time PCR等方法检测超表达Gpr3后对猪卵泡颗粒细胞生长及分化的影响,主要研究结果如下：
1用电子克隆和RACE的方法克隆了猪Gpr3基因的全长序列和含有完整编码框的Gpr6及Gpr12的部分cDNA序列,GenBank登录号分别为HQ606483、HM777010和HM77711,并做生物信息学预测分析,结果表明：猪Gpr3基因的cDNA由2101个核苷酸组成,编码330个氨基酸,分子量为35.2kDa,位于第6号染色体,与牛、犬、人、黑猩猩、小鼠和大鼠的氨基酸相似性分别为96.4%,95.1%,94.9%,94.8%,90.0%和85.4%。它具有典型的七次跨膜结构域,存在多个潜在的磷酸化和糖基化修饰位点,表明它是一个功能活跃的跨膜蛋白,可能参与信号传导、细胞生长调控等过程。另外,猪Gpr3、Gpr6和Gpr12的蛋白序列比对及功能预测分析发现,它们彼此间具有高度的序列同源性和相似的潜在功能,将三者归为同一受体亚家族,称为Gpr3亚家族。
2用real-time PCR和Western blotting的方法检测猪Gpr3基因的组织分布及在卵母细胞成熟过程中的表达模式,结果表明：猪Gpr3基因在大脑、小脑、下丘脑、垂体、心脏、肝脏、脾脏、肺脏、’肾脏、肌肉、脂肪、胸腺、卵巢、输卵管、子宫、睾丸、卵母细胞和颗粒细胞中均有表达,但仅在脑、垂体、肝脏、脂肪、子宫和卵母细胞中大量表达,推测其在猪的神经系统及生殖系统发育和功能维持方面具有重要作用,可能参与猪的脂肪代谢。另外,Gpr3基因在猪卵母细胞体外成熟过程中的表达量呈下降趋势,并且与卵丘扩散程度呈显著的负相关(r=-0.937,P<0.01),表明其可能对卵丘扩散和卵母细胞成熟具有重要作用。成熟促进因子(Maturation promoting factor, MPF)的调节亚基Cyclin B1基因在卵母细胞体外成熟前期的表达量较低(0-24h),后期显著的升高(24-44h),而催化亚基CDK1基因的表达水平在整个培养过程中保持相对稳定,说明MPF可能主要在卵母细胞体外成熟后期发挥作用。
3用免疫组织化学方法检测Gpr3蛋白在9个阶段猪卵巢组织中的表达与定位,结果表明：在胎儿和新生期,Gpr3主要在卵母细胞巢中的卵原细胞、原始卵泡和初级卵泡的卵母细胞中表达；在生后期,Gpr3在腔前卵泡和有腔卵泡的颗粒细胞层、卵丘细胞和卵母细胞胞质中表达,并且在卵母细胞中的表达量最高。另外,在成年猪卵巢的黄体中也有微弱的表达。Real-time PCR和Western blotting结果表明,Gpr3mRNA和蛋白在不同发育阶段猪卵巢中均有表达,表达量呈波浪状变化,在新生及出生后140日龄的表达量最高；在不同品种猪的卵巢中,Gpr3的表达量趋于一致,未见显著性差异；在不同直径猪卵巢卵泡中,Gpr3的表达量随着卵泡直径的增加而上升。猪Gpr3受体在卵巢中的细胞和时期特异性表达模式表明,其可能在猪卵泡发育和黄体形成过程中发挥重要作用。
4为了探究Gpr3的性质功能并筛选其潜在的配体,我们构建了Gpr3真核表达载体及与GFP融合表达载体,用以检测Gpr3在人胚肾(HEK293)细胞中的亚细胞定位、组成性活性、鞘脂类脂质对组成性活性和受体内化的影响。结果表明：在HEK293细胞中,Gpr3的表达引起了腺苷酸环化酶(adenylate cyclase, AC)组成性激活,并且激活程度与完全激活Gs偶联受体的程度相似。而且,鞘氨醇1-磷酸(sphingosine1-phosphate, S1P)可以通过组成性激活的Gpr3受体进一步增加AC的活性。当在HEK239细胞中表达绿色荧光蛋白(green fluorescent protein, GFP)标记的Gpr3受体时发现,绿色荧光仅集中于细胞膜和亚细胞膜中。S1P处理后,通过荧光共聚焦显微镜可以观察到激动剂诱导的受体内化过程。而鞘氨醇(sphingosine, Sph)和鞘磷脂(sphingomyelin, Sphi)不具备以上功能。说明,Gpr3是组成性激活的G蛋白偶联受体,它的组成性活性及激动剂诱导的内化作用受到脂质调节者S1P的调控,表明S1P可能是猪Gpr3受体的潜在激动剂。
5为了研究Gpr3信号通路在猪卵泡颗粒细胞中的作用,本研究从猪卵巢卵泡(3-5mm)内分离颗粒细胞(pGCs)进行体外培养。采用RNAi技术“沉默”Gpr3阻抑其介导的信号通路,以检测Gpr3受体在猪卵泡颗粒细胞生长及分化过程中的作用。结果表明：转染Gpr3特异性的siRNA后,能够有效地抑制颗粒细胞中Gpr3mRNA和蛋白的表达,成功地阻抑了Gpr3介导的信号通路。MTT、流式细胞术及RIA检测的结果表明,阻抑Gpr3信号通路能够促进颗粒细胞增殖,抑制颗粒细胞凋亡,但对颗粒细胞中类固醇激素的合成没有影响。另外,阻抑Gpr3信号通路显著改变了Cyclin B1、 Cyclin D2、Bcl-2、Bax和Gprl2的表达(P<0.05),而对CDK1、CDK4、P450arom、 P450scc和Gpr6的表达没有影响(P>0.05)。
6为了进一步明确Gpr3在猪颗粒细胞中的功能,我们在颗粒细胞中超表达了Gpr3受体,结果表明：超表达Gpr3能显著抑制颗粒细胞的增殖,增加G0/G1期细胞的百分含量,减少S期的细胞,同时降低细胞周期标志蛋白Cyclin B1和CDK1的mRNA表达；超表达Gpr3能显著增加颗粒细胞的凋亡比率,抑制Bcl-2的表达,促进Bax的表达；超表达Gpr3促进了Gpr6的表达；然而,超表达Gpr3不影响雌二醇和孕酮的分泌,并且未显著改变P450arom和P450scc的表达。由此可见,Gpr3信号通路在调控猪卵泡颗粒细胞生长和凋亡过程中具有重要的作用,相关基因表达量的改变为进一步探索Gpr3受体在调节卵泡颗粒细胞生长及凋亡过程的中作用机制奠定了一定的基础。
Mammalian follicular development is a very complex physiological and biochemical cascade process, including recruitment of the primitive follicle, the development of preantral follicle and antral follicle selection, growth and mature or follicle atresia. This procedure can be regulated by a lot of factors, such as hormones and growth factors. It is well known that only a few follicles can reach dominant follicles and ovulation, and more than99%follicles go atresia in mammals. Granulosa cells are key somatic cells in follicles, and play very important roles in oocyte maturation and follicular development. Follicular development is accompanied by growth, proliferation, differentiation, and maturation of granulosa cells. G protein-coupled receptor3(Gpr3) belongs to the G protein-coupled receptor superfamily. Recent study showed that Gpr3regulated follicular development and oocyte maturation through Gs-linked signal pathways in ovarian cells of mice and human. However, the expression pattern in ovary and the roles in follicular granulosa cells of Gpr3are have not yet been well documented in pigs. Therefore, it is immediately required to carry out the further study on the expression pattern of Gpr3and regulatory mechanisms of the Gpr3signaling pathway in the follicular granulosa cells of pigs, which provides possible rationale to selection of mammalian reproductive trait and has great importance to the improvement of reproductive capacity of domestic animals.
In this study, using in silico approach combined with reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE), we cloned the full-length of porcine Gpr3gene and the complete coding sequences of porcine Gpr6and Gpr12genes. Bioinformatics methods were adopted to predict the structure and function of Gpr3, Gpr6and Gpr12protein. Real-time RT-PCR and Western blotting were performed to investigate Gpr3expression pattern in tissues and the whole cumulus-oocyte complexes (COCs) of in vitro maturation (IVM). Cellular localization of Gpr3in the ovaries of50,70and90post coitum (dpc), days1,25,35,70,140and180postpartum (dpp) of commercial pigs were examined by immunohistochemistry (IHC). Time-spatial expression of Gpr3in multi-age, multi-breed ovaries and multi-diameter follicles were detected by Real-time RT-PCR and Western blotting. Subcellular localization, constitutive activity of Gpr3and the effect of sphingolipids on its constitutive activity and ligand-induced receptor internalization were tested using the vectors of pcDNA-Gpr3and pEGFP-Gpr3in HEK293cells. In order to repress Gpr3signaling, the gene of Gpr3was silenced by RNAi, the effects of repressed Gpr3signaling on porcine follicular granulosa cells and underlying molecular mechanism were detected by MTT, FCM, RIA and real-time RT-PCR. The effects of Gpr3overexpression on porcine follicular granulosa cells and underlying molecular mechanism were also detected by MTT, FCM, RIA and real-time RT-PCR.
The main results achieved were as follows:
1The full-length of porcine Gpr3gene and the complete coding sequences of porcine Gpr6and Gprl2genes were cloned by RT-PCR and RACE, and were submitted to GenBank (Accession No. HQ606483, HM777010and HM77711, respectively). Using bioinformatics network resources and relevant software, we predicted that the full sequence of Gpr3gene with its length being2101bp nucleotides, including an open reading frame of993bp, encoded a330amino acid polypeptide with the molecular weight of35.2kDa, localizeg at chromosome6. Comparison of the putative amino acid of porcine orthologs with that of other species showed that porcine Gpr3shared96.4%,95.1%,94.9%,94.8%,90.0%and85.4%homology with Bos taurus (XP612644.2), Canis lupus familiaris (XP544470.1), Homo sapiens (NP005272.1), Pan troglodytes (XP001148989.1), Mus musculus (NP032180.1) and Rattus norvegicus (NP714949.1) respectively, which proved that Gpr3gene was well conserved in the process of evolution. The Gpr3protein contained the typical seven-transmembrane structure of G protein-coupled receptors (GPCRs), including several potential phosphorylation and N-glycosylation sites, suggesting that it might be involved in signal transduction and regulation of cell growth process. Further, on the basis of their high levels of sequence similarity and similar potential roles, Gpr3, Gpr6and Gpr12genes were identified as a subfamily of GPCRs, called Gpr3subfamily of GPCRs.
2Expression patterns of Gpr3in tissues and the whole COCs during IVM were investigated by real-time RT-PCR and Western blotting. The results indicated that Gpr3gene was expressed in tissues of cerebrum, cerebellum, hypothalamus, pituitary, heart, liver, spleen, lung, kidney, muscle, fat, thymus, ovary, oviduct, uterus, testis, oocyte, and granulosa cell at different expression levels, the expression levels of this gene in brain, pituitary, liver, fat, uterus and oocyte being higher than that in other tissues. Since Gpr3mRNA and protein were detected in porcine hypothalamus-pituitary-ovary and testis, it can be speculated that this receptor may play an important role in the neural regulation of sexual and/or reproductive functions and fat metabolism in pigs. Interestingly, the mRNA and protein levels of Gpr3in the whole COCs were down-regulated, and its mRNA expression levels were significantly and negatively correlated with the degrees of cumulus expansion (r=-0.937, P<0.01) during IVM, suggesting its important roles in cumulus expansion and oocyte maturation. Maturation/M-phase promoting factor (MPF) is a complex composed of a regulatory subunit cyclin B1and a catalytic subunit CDK1. Cyclin B1transcripts was up-regulated after24h of maturation, while CDK1mRNA levels were unchanged during IVM, suggesting that MPF might play roles in the later stage of oocyte maturation.
3Cellular localization and expression pattern of Gpr3were investigated by IHC, real-time PCR and Western blotting in the ovaries of pigs. The results showed that Gpr3protein was primarily expressed in the oogonia in egg nest and the oocyte in primodial and primary follicles of the fetal and neonatal pigs. In postnatal pigs, Gpr3protein was expressed mainly in the granulosa cell layer, cumulus cell and cytoplasm of oocytes. Furthermore, the immunostaining for Gpr3in cytoplasm of oocytes was the most intensive. In additional, the staining intensity was faintly presented in the corpora lutea of the ovary in adult pigs. The results of real-time PCR and Western blotting indicated that Gpr3mRNA and protein were both presented in the different ages of ovaries, and the expression levels were wave-changed from postpartum1to180days. The expression levels of Gpr3in the1-dpp-old and140-dpp-old ovaries were higher than that of other age ovaries. There was no significant difference among three tested breeds at the expression level of Gpr3in the ovary. Moreover, both mRNA and protein levels of Gpr3were up-regulated significantly during follicle growth. The stage-and cell-specific expression pattern of Gpr3in the porcine ovary suggested that Gpr3might play an important role in the process of entire follicular development and luteinization.
4In order to understand the properties and functions of Gpr3, by which to screen its potential ligands, the vectors of pcDNA-Gpr3and pEGFP-Gpr3were constructed for checking the subcellular localization, constitutive activity of Gpr3and the effect of sphingolipids on its constitutive activity and ligand-induced receptor internalization in HEK293cells. The results showed that expression of porcine Gpr3in HEK293cells resulted in constitutive activation of adenylate cyclase (AC) similar in amplitude to that produced by fully stimulated Gs-coupled receptors. Moreover, sphingosine1-phosphate (SIP) could increase AC activation via the constitutively active Gpr3receptor. When expressed in HEK293cells, GFP-labeled Gpr3protein was shown to be localized in the plasmalemma and subcellular membranes. After SIP treatment, agonist-mediated intemalization could be visualized by confocal microscopy. However, sphingosine (Sph) and sphingomyelin (Sphi) had no ability like that of S1P. In short, our findings suggested that the porcine Gpr3is a constitutively active G protein-coupled receptor. Constitutive activation of AC and agonist-mediated intemalization of Gpr3receptor could be modulated by the SIP, suggesting that SIP might act as an activator for porcine Gpr3receptor.
5To demonstrate the effects of Gpr3signaling pathways on growth and differentiation of porcine granulosa cells (pGCs), pGCs were isolated from3-5mm antral follicles in diameter and cultured in vitro. A strategy of RNAi-mediated gene silencing of Gpr3was used to repress endogenous Gpr3signaling in cells. The results indicated that GprJ-siRNA causes specific inhibition of Gpr3mRNA and protein expression after transfection, which successfully repressed endogenous Gpr3signaling in pGCs. Repressed endogenous Gpr3signaling significantly promoted growth and inhibited apoptosis of pGCs, but no effect was shown on steroidogenesis in pGCs. In addition, repressed Gpr3signaling significantly changed the mRNA expression of Cyclin B1, Cyclin D2, Bcl-2, Bax and Gpr12(P<0.05), but there is no change in the expression of CDK1, CDK4, P450arom, P450scc and Gpr6(P>0.05).
6To further confirm the roles of Gpr3in pGCs, Gpr3overexpression was performed in pGCs. The results showed that Gpr3overexpression significantly inhibited porcine GCs proliferation, increased the proportion of G0/G1-phase cells, and decreased the cells of S-phase and the mRNA expression of Cyclin B1and CDK1; Gpr3overexpression significantly induced apoptosis of porcine GCs, decreased the expression of Bcl-2, and increased the expression of Bax; Gpr3overexpression significantly increased the expression of Gpr6. However, there was no effect of Gpr3overexpression on steroidogenesis and related genes in pGCs. These results implied that Gpr3signaling play an important role in pGCs, and the change of genes related to cell growth and apoptosis were provided a basis for further research on the regulatory mechanisms of porcine Gpr3gene in pGCs.
引文
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