Negative feedback governs gonadotrope frequency-decoding of gonadotropin releasing hormone pulse-frequency.
Negative feedback governs gonadotrope frequency-decoding of gonadotropin releasing hormone pulse-frequency.
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DOI：
10.1371/journal.pone.0007244
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发表时间：
2009-09-29
期刊：
影响因子：
3.7
通讯作者：
Melamed P
中科院分区：
文献类型：
--
作者：
Lim S;Pnueli L;Tan JH;Naor Z;Rajagopal G;Melamed P
促性腺激素亚基的合成由下丘脑的脉冲性促性腺激素释放激素（GnRH）指导，GnRH脉冲的频率决定了共同α亚基、促性腺激素β亚基（LHβ）和促卵泡激素β亚基（FSHβ）的差异表达。三种丝裂原活化蛋白激酶（MAPK），ERK 1/2，JNK和p38，对这些亚基基因中的每一个的表达具有独特的和组合的贡献。在这项研究中，使用实验和计算的方法，我们发现，双特异性磷酸酶调节的活性的三个MAPKs通过负反馈是必需的，并形成解码的脉动GnRH的频率的基础。第四种MAPK ERK 5也被GnRH激活。研究发现ERK 5可刺激FSHβ启动子活性，增加FSHβ mRNA水平，并增强其对低GnRH脉冲频率的偏好。后者是通过增加MAPK依赖性的数量来增强FSHβ基因表达的超敏感行为，以及通过调节JNK激活对GnRH受体（GnRH-R）的前馈效应来实现的。我们的研究结果有助于了解改变GnRH脉冲频率在控制垂体促性腺激素转录中的作用，垂体促性腺激素转录是调节生殖的一个重要方面。脉动刺激和振荡信号是许多生物过程不可或缺的，并且对脉动性被解码的机制的阐明解释了相同的刺激如何在单个细胞中导致各种结果。
The synthesis of the gonadotropin subunits is directed by pulsatile gonadotropin-releasing hormone (GnRH) from the hypothalamus, with the frequency of GnRH pulses governing the differential expression of the common α-subunit, luteinizing hormone β-subunit (LHβ) and follicle-stimulating hormone β-subunit (FSHβ). Three mitogen-activated protein kinases, (MAPKs), ERK1/2, JNK and p38, contribute uniquely and combinatorially to the expression of each of these subunit genes. In this study, using both experimental and computational methods, we found that dual specificity phosphatase regulation of the activity of the three MAPKs through negative feedback is required, and forms the basis for decoding the frequency of pulsatile GnRH. A fourth MAPK, ERK5, was shown also to be activated by GnRH. ERK5 was found to stimulate FSHβ promoter activity and to increase FSHβ mRNA levels, as well as enhancing its preference for low GnRH pulse frequencies. The latter is achieved through boosting the ultrasensitive behavior of FSHβ gene expression by increasing the number of MAPK dependencies, and through modulating the feedforward effects of JNK activation on the GnRH receptor (GnRH-R). Our findings contribute to understanding the role of changing GnRH pulse-frequency in controlling transcription of the pituitary gonadotropins, which comprises a crucial aspect in regulating reproduction. Pulsatile stimuli and oscillating signals are integral to many biological processes, and elucidation of the mechanisms through which the pulsatility is decoded explains how the same stimulant can lead to various outcomes in a single cell.
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