PI3K p110delta催化亚基在小鼠卵巢卵泡生长中的功能研究
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摘要
在哺乳动物出生前后，卵巢中就形成了原始卵泡并处于休眠状态，在人类这个状态能维持长达数十年之久。原始卵泡在一定的调控机制下可以被激活成初级卵泡并开始生长，在各种激素和生长因子包括雌激素（estrogen）、卵泡刺激素（FSH）和胰岛素样生长因子（insulin-like growth factor1，IGF1）的作用下逐步经历次级卵泡、早窦卵泡和有腔卵泡，在青春期开始后，在FSH和LH的相继作用下卵泡发育至排卵前卵泡并发生排卵，卵泡生长发育过程的正常进行并排出正常数量和质量的卵细胞是维持雌性生育力的关键因素。各种激素和生长因子调控卵泡生长的分子机制和信号通路一直是研究的热点，近年报道PI3K信号通路在原始卵泡存活和激活中发挥重要调控作用，而在FSH诱导的卵泡成熟过程中也能激活颗粒细胞中的PI3K信号通路，但是PI3K通路的激活在卵泡的生长成熟中是否起着必不可少的作用目前还没有确切的证据。
为了更深入的了解PI3K通路在卵巢卵泡生长中的作用，本研究关注了PI3K信号通路的上游分子PI3K家族中classⅠ催化亚基的p110delta亚型（由Pik3cd基因所编码）在卵泡生长与维持雌鼠生育力中的作用。首先我们发现p110delta在卵巢组织中有较高的表达，主要表达于颗粒细胞和卵细胞，进一步交配实验发现Pik3cd基因敲除的小鼠和对照组相比生育力下降，表现为每胎产仔数显著下降，且卵巢中的成熟卵泡数减少、凋亡卵泡增多，并且对于外源性促性腺激素PMSG（模拟内源性FSH效应）的反应性很弱。卵巢移植实验显示Pik3cd基因敲除的卵巢在体外同样对FSH的刺激没有反应，几乎没有卵泡生长，证明了卵泡成熟障碍的表型是卵巢内源性而不是由于全身其它系统的问题而引起的。此外，E2能诱导对照组小鼠卵巢中腔前卵泡的生长和颗粒细胞的增殖增强，而Pik3cd基因敲除卵巢对于E2反应也很低下，不能引起卵泡的生长和颗粒细胞增殖。实验证实在对照组中FSH和E2给药后都能激活卵巢中的PI3K信号通路，而在敲除小鼠卵巢中PI3K通路的激活阻滞。另外，Pik3cd基因敲除后卵巢中原始卵泡激活和卵细胞减数分裂成熟并没有受到影响。
以上的实验结果说明，PI3K信号通路在介导外源性激素如FSH和E2引起的卵泡生长中起了很重要的作用，而p110delta催化亚基是介导卵巢颗粒细胞中PI3K信号通路的一个非常重要的亚型，其缺失后会影响颗粒细胞的生长和增殖，而可能不是卵细胞PI3K通路中的必要亚型。
In the mammalian ovary, primordial follicles are generated early in life andremain dormant for prolonged periods. Their growth resumes via primordial follicleactivation, and then continue to grow until the preovulatory stage under theregulation of hormones and growth factors, such as estrogen, follicle stimulatinghormone (FSH), and insulin-like growth factor-I (IGF-I). Both FSH and IGF-Iactivate the PI3K/Akt signaling pathway in granulosa cells (GCs), yet it remainsinconclusive whether PI3K pathway is crucial for follicle growth. In this study, wehave investigated the p110delta-isoform (encoded for by the Pik3cd gene) of thePI3K catalytic subunit expression in the mouse ovary and its function in fertility.Pik3cd null females were subfertile, had fewer growing follicles and more atreticantral follicles in the ovary and responded poorly to exogenous gonadotropins whencompared to controls. Ovary transplantation assay showed Pik3cd null ovariesresponded poorly to FSH stimulation in-vitro, which confirmed the follicle growthdefect was intrinsically ovarian. In addition, estradiol (E2)-stimulated follicle growthand GC proliferation in preantral follicles were impaired in Pik3cd null ovaries. FSHand E2substantially activated the PI3K/Akt pathway in GCs of control mice, but notin those of Pik3cd null mice. However, primordial follicle activation and oocytemeiotic maturation were not affected by Pik3cd knockout. Thus, thep110delta-isoform of the PI3K catalytic subunit is a key component of the PI3K pathway for both FSH and E2-stimulated follicle growth in ovarian granulosa cells,but is not required for primordial follicle activation and oocyte development.
为了更深入的了解PI3K通路在卵巢卵泡生长中的作用，本研究关注了PI3K信号通路的上游分子PI3K家族中classⅠ催化亚基的p110delta亚型（由Pik3cd基因所编码）在卵泡生长与维持雌鼠生育力中的作用。首先我们发现p110delta在卵巢组织中有较高的表达，主要表达于颗粒细胞和卵细胞，进一步交配实验发现Pik3cd基因敲除的小鼠和对照组相比生育力下降，表现为每胎产仔数显著下降，且卵巢中的成熟卵泡数减少、凋亡卵泡增多，并且对于外源性促性腺激素PMSG（模拟内源性FSH效应）的反应性很弱。卵巢移植实验显示Pik3cd基因敲除的卵巢在体外同样对FSH的刺激没有反应，几乎没有卵泡生长，证明了卵泡成熟障碍的表型是卵巢内源性而不是由于全身其它系统的问题而引起的。此外，E2能诱导对照组小鼠卵巢中腔前卵泡的生长和颗粒细胞的增殖增强，而Pik3cd基因敲除卵巢对于E2反应也很低下，不能引起卵泡的生长和颗粒细胞增殖。实验证实在对照组中FSH和E2给药后都能激活卵巢中的PI3K信号通路，而在敲除小鼠卵巢中PI3K通路的激活阻滞。另外，Pik3cd基因敲除后卵巢中原始卵泡激活和卵细胞减数分裂成熟并没有受到影响。
以上的实验结果说明，PI3K信号通路在介导外源性激素如FSH和E2引起的卵泡生长中起了很重要的作用，而p110delta催化亚基是介导卵巢颗粒细胞中PI3K信号通路的一个非常重要的亚型，其缺失后会影响颗粒细胞的生长和增殖，而可能不是卵细胞PI3K通路中的必要亚型。
In the mammalian ovary, primordial follicles are generated early in life andremain dormant for prolonged periods. Their growth resumes via primordial follicleactivation, and then continue to grow until the preovulatory stage under theregulation of hormones and growth factors, such as estrogen, follicle stimulatinghormone (FSH), and insulin-like growth factor-I (IGF-I). Both FSH and IGF-Iactivate the PI3K/Akt signaling pathway in granulosa cells (GCs), yet it remainsinconclusive whether PI3K pathway is crucial for follicle growth. In this study, wehave investigated the p110delta-isoform (encoded for by the Pik3cd gene) of thePI3K catalytic subunit expression in the mouse ovary and its function in fertility.Pik3cd null females were subfertile, had fewer growing follicles and more atreticantral follicles in the ovary and responded poorly to exogenous gonadotropins whencompared to controls. Ovary transplantation assay showed Pik3cd null ovariesresponded poorly to FSH stimulation in-vitro, which confirmed the follicle growthdefect was intrinsically ovarian. In addition, estradiol (E2)-stimulated follicle growthand GC proliferation in preantral follicles were impaired in Pik3cd null ovaries. FSHand E2substantially activated the PI3K/Akt pathway in GCs of control mice, but notin those of Pik3cd null mice. However, primordial follicle activation and oocytemeiotic maturation were not affected by Pik3cd knockout. Thus, thep110delta-isoform of the PI3K catalytic subunit is a key component of the PI3K pathway for both FSH and E2-stimulated follicle growth in ovarian granulosa cells,but is not required for primordial follicle activation and oocyte development.
引文
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