C型尿钠肽在动物卵巢表达及对生殖机能影响的研究进展

Recent Advances in Research of the Expression and Role of C-Type Natriuretic Peptide as a Regulator in Control of Animal Ovary Performance

C型尿钠肽(C-type natriuretic peptide,Cnp)为尿钠肽家族成员之一,广泛分布于动物大脑、肾脏、心脏及血管等组织,具有维持心血管系统功能稳态、调控细胞增殖及促进骨骼生长等功能。普遍认为哺乳动物有3种钠尿肽受体(Natriuretic peptide receptor,NPR):NPR1,NPR2和NPR3。Cnp主要通过结合NPR2受体激活下游信号通路,发挥生物学作用。Cnp信号传导通路的组成成分主要包括:配体(Cnp)、跨膜受体(NPR2)及cGMP等。当Cnp分子与跨膜受体NPR2结合后,使受体的激酶同型区域(kinase homology domain,KHD)构象发生变化,进而激活鸟苷酸环化酶,将GTP转化为cGMP后激活下游信号通路。目前,许多研究表明Cnp及受体在雌性动物卵巢上表达模式相似,Cnp主要在卵泡壁层颗粒细胞上表达,NPR2受体主要在卵丘颗粒细胞上表达。另外,动物体内卵泡生长期间,Cnp和受体Npr2表达受激素调控,FSH通过雌激素介导促进卵泡颗粒细胞Cnp和受体Npr2表达;同时卵母细胞通过分泌卵母细胞分泌因子促进了颗粒细胞Npr2表达。LH可能通过表皮生长因子信号通路降低卵泡颗粒细胞Cnp和受体Npr2表达。值得注意的是,研究表明Cnp与FSH功能类似能够促进动物卵泡发育,有利于卵丘颗粒细胞的形成,并能诱导一些与卵泡成熟和类固醇合成相关的颗粒细胞基因表达,揭示卵泡颗粒细胞分泌的Cnp与FSH具有类似的功能,作用于颗粒细胞上的受体分别经由cGMP和cAMP的信号通路影响颗粒细胞基因表达,刺激卵泡生长,促进卵母细胞成熟。另外,近年研究揭示Cnp是动物体内维持卵母细胞减数分裂阻滞的关键物质,卵泡壁层颗粒细胞分泌的Cnp,作用于卵丘颗粒细胞上的受体NPR2,激活鸟甘酸环化酶后将cGTP转化为cGMP,cGMP进入卵母细胞后抑制磷酸二酯酶phosphodiesterase,PDE)的活性,维持卵母细胞内高水平的cAMP,卵母细胞内高水平的cAMP通过激活蛋白激酶A(protein kinase A,PKA)使成熟促进因子(maturation promoting factor,MPF)的催化亚基磷酸化,进而抑制MPF的活性、维持减数分裂阻滞,但对裸卵没有影响,说明Cnp通过作用卵丘颗粒细胞间接影响卵母细胞减数分裂成熟。此外,研究表明Cnp体外前处理卵丘卵母细胞复合体,有利于卵母细胞胞质成熟,提高了成熟受精后的发育能力。综上,动物体内卵泡生长期间,卵巢内产生的Cnp可能通过影响颗粒细胞的正常功能,在维持卵母细胞减数分裂阻滞的同时促进胞质成熟,保证成熟受精后具有较高的发育能力。基于此,Cnp在用作生理性的减数分裂阻滞剂增强家畜卵母细胞体外发育方面将具有重要的应用前景。因此,论文综述了Cnp结构、信号转导通路、在动物卵巢上表达及对卵巢生殖机能的影响。

C-type natriuretic peptide （Cnp）, a member of the natriuretic peptide family of structurally related peptides, is widely distributed in animal brain, kidney, heart and vascular tissues with important roles in cardiovascular homeostasis, regulation of cell proliferation and skeletal development. It is generally believed that there are three known natriuretic peptide receptors （NPR） in mammals： NPR1, NPR1, and NPR3. Cnp exerts its biological actions by the preferentially activation of NPR2. The components of the Cnp signaling pathway mainly include ligand （Cnp）, transmembrane receptor （NPR2） and cGMP. Binding of Cnp to NPR2 results in the change of receptor kinase homology domain conformation, which can further activate downstream pathway through stimulation of cGMP production by the activation of receptor guanylate cyclase. At present, some studies have shown that Cnp is expressed predominantly by mural granulosa cells, which line the inside of the follicular wall, whereas Npr2 is expressed predominantly by cumulus cells, indicating a similar pattern of Cnp and Npr2 expression in female animal ovary. In addition, the expression of Cnp and Npr2 is hormonally regulated during animal follicular growth in vivo. FSH- promoted expression of Cnp and Npr2 is mediated by estradiol. Meanwhile, Oocyte-derived paracrine factors promot expression of Npr2 in cumulus cells. LH- reduced expression of Cnp and Npr2 probably is due to activation of EGF signal pathway. Notably, research showed that Cnp, similar to FSH, can induce the expression of diverse ovarian genes important for follicle maturation and steroidogenesis, which is beneficial to cumulus oophorus formation, thereby promote follicular development, indicating that similar to the known follicle-stimulating and oocyte maturation effects of FSH, and Cnp/FSH exerts their biological actions via cGMP/cAMP signal pathway, respectively. Besides, recent studies have revealed that Cnp, secreted by mural granulosa cells, plays an essential role in maintaining meiotic arrest of oocyte. Cnp exerts its biological action as a local factor by binding to NPR2 in cumulus cells, followed by the production of cGMP via the guanylyl cyclase catalytic domains of NPR2, then cGMP diffuses into the oocyte from companion cumulus cells via gap junctions, and inhibits oocyte PDE activity and cAMP hydrolysis, at the same time, higher level of cAMP inhibits oocyte MPF activity, subsequently preventing meiotic resumption of oocyte; whereas Cnp does not affect meiotic maturation of naked oocytes, suggesting the indirect effect of Cnp on meiotic maturation of oocyte by acting as a regulator to cumulus cells. Additionally, pre-treatment of oocytes with Cnp exerts a beneficial effect on cytoplasmic maturation, thereby enhances the developmental capacity of oocyte following in vitro maturation. To sum up, Cnp produced within the ovary might maintain meiotic arrest of oocyte, as well promote cytoplasmic maturation of oocyte by affecting the physiological function of cumulus cells during animal follicular growth, which ensure the higher capability of development after oocyte maturation and fertilization. In light of the findings above, Cnp may be of special importance in the promotion of oocyte development in vitro as one meiotic inhibitor in domestic animals. Hence, this paper reviewed the structure of Cnp, its signal transduction pathway and expression in ovary as one of functional molecules that modulate ovary function in animals.