Zhang Wenqiang, Chen Qian, Yang Ye, Liu Wei, Zhang Meijia, Xia Guoliang, Wang Chao
State Key Laboratory of Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, People's Republic of China.
Mol Reprod Dev. 2014 Nov;81(11):1030-41. doi: 10.1002/mrd.22424. Epub 2014 Oct 27.
The epidermal growth factor (EGF) network, induced by luteinizing hormone (LH), plays an essential role during the regulation of oocyte maturation, cumulus expansion, and ovulation. Binding of brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) to natriuretic receptor 2 (NPR2) generates cyclic guanosine monophosphate (cGMP), a key inhibitor that sustains porcine oocyte meiotic arrest. This correlation suggests that LH interacts with natriuretic-peptide signaling, possibly via the EGF network, to promote porcine meiotic resumption. In testing this hypothesis, we found that the majority of porcine oocytes remain arrested in the germinal-vesicle stage after 44 hr of co-culturing cumulus-oocyte complexes with 10(7) granulosa cells, which secreted active BNP and CNP; these natriuretic peptides associate with NPR2 on cumulus cells, thereby inhibiting porcine oocyte maturation. This inhibitory effect of BNP and CNP was relieved by EGF-like growth factors, whose expression naturally increases in granulosa cells 18 hr after human chorionic gonadotropin injection. LH and the EGF-like peptide amphiregulin (AREG) decreased BNP and CNP production in granulosa cells and down-regulated NPR2 expression in cumulus cells, which together decreased oocyte cGMP to levels that permit meiotic resumption. The effects of AREG on the gene expression of natriuretic-peptide signaling components and on oocyte maturation were completely blocked by the EGF receptor kinase inhibitor AG1478; the effect of LH, however, was only partially reversed by AG1478. Based on these results, LH regulates natriuretic-peptide signaling, although other pathways also cooperate with the EGF network to induce porcine oocyte maturation.
由促黄体生成素（LH）诱导的表皮生长因子（EGF）网络在卵母细胞成熟、卵丘扩展和排卵的调节过程中发挥着重要作用。脑钠肽（BNP）和C型钠肽（CNP）与钠尿肽受体2（NPR2）结合会生成环磷酸鸟苷（cGMP），这是维持猪卵母细胞减数分裂阻滞的关键抑制剂。这种关联表明，LH可能通过EGF网络与钠尿肽信号传导相互作用，以促进猪的减数分裂恢复。在验证这一假设时，我们发现，将卵丘-卵母细胞复合体与分泌活性BNP和CNP的10⁷颗粒细胞共同培养44小时后，大多数猪卵母细胞仍停滞在生发泡期；这些钠尿肽与卵丘细胞上的NPR2结合，从而抑制猪卵母细胞成熟。EGF样生长因子可缓解BNP和CNP的这种抑制作用，人绒毛膜促性腺激素注射18小时后，颗粒细胞中其表达自然增加。LH和EGF样肽双调蛋白（AREG）可降低颗粒细胞中BNP和CNP的产生，并下调卵丘细胞中NPR2的表达，共同使卵母细胞cGMP降至允许减数分裂恢复的水平。EGF受体激酶抑制剂AG1478完全阻断了AREG对钠尿肽信号传导成分基因表达和卵母细胞成熟的影响；然而，AG1478仅部分逆转了LH的作用。基于这些结果，LH调节钠尿肽信号传导，尽管其他途径也与EGF网络协同诱导猪卵母细胞成熟。
