G Protein-Coupled Receptor 30 Mediates Estrogen-Induced Proliferation of Primordial Germ Cells Via EGFR/Akt/β-Catenin Signaling Pathway
G Protein-Coupled Receptor 30 Mediates Estrogen-Induced Proliferation of Primordial Germ Cells Via EGFR/Akt/β-Catenin Signaling Pathway
复制标题
DOI：
10.1210/en.2012-1200
复制
发表时间：
2012-07-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Caiqiao
中科院分区：
文献类型：
--
作者：
Ge, Chutian;Yu, Minli;Zhang, Caiqiao
在脊椎动物中，雌激素是出生后性腺正常发育和功能所必需的。然而，雌激素是否能够调节胎儿生殖细胞的发育仍不清楚。在这里，我们发现，出乎意料的是，鸡原始生殖细胞（PGC）缺乏雌激素受体α/β仍然增殖响应17 β-雌二醇（E-2）。这是由于存在于PGC上的G蛋白偶联受体30（GPR 30）直接结合E-2的能力。敲低实验表明，GPR 30是E-2刺激的PGC增殖所必需的。此外，这种雌激素诱导的GPR 30激活被揭示通过G β γ亚基蛋白依赖性和通过基质金属蛋白酶依赖性的表皮生长因子受体的反式激活而发生。表皮生长因子受体激活导致一系列细胞内事件，包括磷脂酰肌醇3-激酶/丝氨酸-苏氨酸激酶/β-连环蛋白途径的激活，随后诱导c-fos、c-myc、细胞周期蛋白D1/E和B细胞淋巴瘤2表达，以及抑制B细胞淋巴瘤2相关X蛋白表达和半胱天冬酶3/9活性。这最终导致细胞凋亡减少和PGC增殖增加。总的来说，这些研究结果提供了新的见解雌激素作用于PGC增殖的动态机制，并表明，E-2/GPR 30信号可能在调节胎儿生殖细胞发育中发挥重要作用，特别是在性分化前的阶段。（内分泌学153：3504-3516，2012）
In vertebrates, estrogens are required for the normal development and function of postnatal gonads. However, it remains unclear whether estrogens are able to modulate development of the fetal germ cells. Here, we show that, unexpectedly, chicken primordial germ cells (PGC) lacking estrogen receptor alpha/beta still proliferate in response to 17 beta-estradiol (E-2). This is due to the capacity of G protein-coupled receptor 30 (GPR30), existing on PGC, to directly bind E-2. Knockdown experiments suggest that GPR30 is required for E-2-stimulated PGC proliferation. Furthermore, this estrogen-induced activation of GPR30 is revealed to occur through the G beta gamma-subunit protein-dependent and through the matrix metalloproteinase-dependent transactivation of the epidermal growth factor receptor. Epidermal growth factor receptor activation results in a series of intracellular events, including activation of the phosphatidylinositol 3-kinase/serine-threonine kinase/beta-catenin pathway, which are followed by the induction of c-fos, c-myc, cyclin D1/E, and B-cell lymphoma 2 expression, and the inhibition of B-cell lymphoma 2-associated X protein expression and caspase3/9 activity. This eventually leads to decreased apoptosis and increased PGC proliferation. Collectively, these findings offer novel insights into the dynamic mechanism of estrogen action on PGC proliferation and suggest that E-2/GPR30 signaling might play an important role in regulating fetal germ cell development, particularly at the stage before sexual differentiation. (Endocrinology 153: 3504-3516, 2012)