Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation
Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation
复制标题
DOI：
10.1073/pnas.1213594110
复制
发表时间：
2013-04-02
影响因子：
11.1
通讯作者：
Kim, Kyungjin
中科院分区：
文献类型：
--
作者：
Choe, Han Kyoung;Kim, Hee-Dae;Kim, Kyungjin
下丘脑促性腺激素释放激素（GnRH）的脉冲式释放对垂体促性腺激素功能至关重要。虽然GnRH脉冲性分泌的重要性已经被认识了几十年，但下丘脑神经网络中GnRH脉冲产生的机制仍然难以捉摸。在这里，我们证明了超昼夜节律的GnRH基因转录在单个GnRH神经元使用培养的下丘脑切片制备的转基因小鼠表达GnRH启动子驱动的不稳定的荧光素酶报告。虽然在每个GnRH神经元的GnRH启动子活性表现出一个ultradian模式的振荡周期类似于10小时，GnRH神经元培养物表现出部分同步的GnRH转录活性爆发在类似的2小时的时间间隔。令人惊讶的是，kisspeptin，一种有效的GnRH促分泌素，脉冲给药，引起显着的同步激活GnRH基因转录与脉冲GnRH分泌的强烈刺激。我们还讨论了昼夜节律和超昼夜节律之间的层次相互作用的问题，通过使用Bmal1缺陷小鼠与缺陷的生物钟。昼夜分子振荡器几乎不影响GnRH转录的基础超昼夜振荡，但大量参与了kisspeptin诱发的GnRH神经元反应。总之，我们已经清楚地表明，在下丘脑GnRH神经元群体中GnRH基因转录的同步爆发与神经激素的分泌有关，从而提供了对GnRH脉冲产生的见解。
Pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH) is essential for pituitary gonadotrope function. Although the importance of pulsatile GnRH secretion has been recognized for several decades, the mechanisms underlying GnRH pulse generation in hypothalamic neural networks remain elusive. Here, we demonstrate the ultradian rhythm of GnRH gene transcription in single GnRH neurons using cultured hypothalamic slices prepared from transgenic mice expressing a GnRH promoter-driven destabilized luciferase reporter. Although GnRH promoter activity in each GnRH neuron exhibited an ultradian pattern of oscillations with a period of similar to 10 h, GnRH neuronal cultures exhibited partially synchronized bursts of GnRH transcriptional activity at similar to 2-h intervals. Surprisingly, pulsatile administration of kisspeptin, a potent GnRH secretagogue, evoked dramatic synchronous activation of GnRH gene transcription with robust stimulation of pulsatile GnRH secretion. We also addressed the issue of hierarchical interaction between the circadian and ultradian rhythms by using Bmal1-deficient mice with defective circadian clocks. The circadian molecular oscillator barely affected basal ultradian oscillation of GnRH transcription but was heavily involved in kisspeptin-evoked responses of GnRH neurons. In conclusion, we have clearly shown synchronous bursts of GnRH gene transcription in the hypothalamic GnRH neuronal population in association with episodic neurohormone secretion, thereby providing insight into GnRH pulse generation.