Molecular basis for the activation of gonadotropin-inhibitory hormone gene transcription by corticosterone.
Molecular basis for the activation of gonadotropin-inhibitory hormone gene transcription by corticosterone.
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DOI：
10.1210/en.2013-2076
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发表时间：
2014-02
期刊：
影响因子：
4.8
通讯作者：
You Lee Son;T. Ubuka;M. Narihiro;Yujiro Fukuda;I. Hasunuma;Kazutoshi Yamamoto;D. Belsham;K. Tsutsui
中科院分区：
文献类型：
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作者：
You Lee Son;T. Ubuka;M. Narihiro;Yujiro Fukuda;I. Hasunuma;Kazutoshi Yamamoto;D. Belsham;K. Tsutsui
应激对生殖功能的抑制作用可能是由高浓度的循环糖皮质激素 (GC) 通过 GC 受体 (GR) 介导的。促性腺激素抑制激素（GnIH）是一种抑制促性腺激素分泌的下丘脑神经肽。 GnIH 可能介导应激引起的生殖功能障碍。然而，目前尚不清楚GC结合的GR是否直接参与GnIH转录。在这里，我们证明了 GR mRNA 在鹌鹑室旁核 GnIH 神经元中的定位，表明 GC 可以直接调节 GnIH 转录。接下来我们发现，皮质酮 (CORT) 治疗 24 小时会增加鹌鹑间脑中的 GnIH mRNA 表达。我们使用源自大鼠下丘脑的表达 GnIH 的神经元细胞系 rHypoE-23 进一步研究了 CORT 激活 GnIH 转录的机制。我们发现，CORT 处理 24 小时后，rHypoE-23 细胞中 GR mRNA 表达增加，GnIH mRNA 表达增加。我们最终表征了 CORT 刺激的大鼠 GnIH 基因的启动子活性。通过DNA缺失分析，我们在GnIH前体编码区上游2000-1501 bp处鉴定了一个CORT响应区。该区域包含 2 个位于 -1665 和 -1530 bp 的 GC 响应元件 (GRE)。 -1530 GRE 的突变消除了 CORT 响应能力。我们还在包含 -1530 GRE 的 GnIH 启动子区域发现了 CORT 刺激的 GR 募集。这些结果证明 CORT 通过将 GR 募集至其启动子来直接诱导 GnIH 转录，为应激下 GnIH 转录激活提供了假定的分子基础。
The inhibitory effect of stress on reproductive function is potentially mediated by high concentrations of circulating glucocorticoids (GCs) acting via the GC receptor (GR). Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that inhibits gonadotropin secretion. GnIH may mediate stress-induced reproductive dysfunction. However, it is not yet known whether GC-bound GR is directly involved in GnIH transcription. Here, we demonstrated the localization of GR mRNA in GnIH neurons in the paraventricular nucleus of quail, suggesting that GC can directly regulate GnIH transcription. We next showed that 24 hours of treatment with corticosterone (CORT) increase GnIH mRNA expression in the quail diencephalon. We further investigated the mechanism of activation of GnIH transcription by CORT using a GnIH-expressing neuronal cell line, rHypoE-23, derived from rat hypothalamus. We found the expression of GR mRNA in rHypoE-23 cells and increased GnIH mRNA expression by 24 hours of CORT treatment. We finally characterized the promoter activity of rat GnIH gene stimulated by CORT. Through DNA deletion analysis, we identified a CORT-responsive region at 2000-1501 bp upstream of GnIH precursor coding region. This region included 2 GC response elements (GREs) at -1665 and -1530 bp. Mutation of -1530 GRE abolished CORT responsiveness. We also found CORT-stimulated GR recruitment at the GnIH promoter region containing the -1530 GRE. These results provide a putative molecular basis for transcriptional activation of GnIH under stress by demonstrating that CORT directly induces GnIH transcription by recruitment of GR to its promoter.