Clarkson Jenny, Boon Wah Chin, Simpson Evan R, Herbison Allan E
Centre for Neuroendocrinology, Department of Physiology, University of Otago, Dunedin, New Zealand.
Endocrinology. 2009 Jul;150(7):3214-20. doi: 10.1210/en.2008-1733. Epub 2009 Mar 19.
The regulation of GnRH neurons by kisspeptin is critical for normal puberty onset in mammals. In the rodent the kisspeptin neurons innervating GnRH neurons are thought to reside in the rostral periventricular area of the third ventricle (RP3V). Using kisspeptin immunocytochemistry we show that kisspeptin peptide expression in the RP3V of female mice begins around postnatal d 15 (P15) and rapidly increases to achieve adult-like levels by P30, the time of puberty onset. Ovariectomy of female pups at P15 resulted in a 70-90% reduction (P < 0.01) in kisspeptin peptide expression within the RP3V of P30 or P60 mice. Replacement of 17-beta-estradiol (E2) in P15-ovariectomized mice from P15-30 or P22-30 resulted in a complete restoration of kisspeptin peptide expression in the RP3V (P < 0.01). Kisspeptin-immunoreactive fibers throughout the hypothalamus, including the arcuate nucleus, followed the same pattern of estrogen-dependent expression. To test the absolute necessity of estrogen for kisspeptin expression in the RP3V, aromatase knockout mice were examined. Kisspeptin-immunoreactive cells were detected in the arcuate nucleus, but there was a complete absence of kisspeptin peptide in RP3V neurons of aromatase knockout adult females. These results demonstrate that E2 is essential for the prepubertal development of kisspeptin peptide within RP3V neurons and suggest that an E2-kisspeptin positive feedback mechanism exists before puberty. This implies that RP3V kisspeptin neurons are E2-dependent amplifiers of GnRH neuron activity in the prepubertal period.
在哺乳动物中，kisspeptin对促性腺激素释放激素（GnRH）神经元的调节对于正常青春期启动至关重要。在啮齿动物中，支配GnRH神经元的kisspeptin神经元被认为位于第三脑室室周吻侧区（RP3V）。通过kisspeptin免疫细胞化学方法，我们发现雌性小鼠RP3V中的kisspeptin肽表达在出生后第15天（P15）左右开始，并迅速增加，到青春期启动时间P30时达到成年水平。在P15对雌性幼崽进行卵巢切除，导致P30或P60小鼠RP3V内的kisspeptin肽表达降低70 - 90%（P < 0.01）。在P15 - 30或P22 - 30期间，给P15卵巢切除的小鼠补充17 - β - 雌二醇（E2），可使RP3V中的kisspeptin肽表达完全恢复（P < 0.01）。下丘脑各处包括弓状核的kisspeptin免疫反应纤维遵循相同的雌激素依赖性表达模式。为了测试雌激素对RP3V中kisspeptin表达的绝对必要性，对芳香化酶基因敲除小鼠进行了检查。在弓状核中检测到kisspeptin免疫反应细胞，但芳香化酶基因敲除成年雌性小鼠的RP3V神经元中完全没有kisspeptin肽。这些结果表明，E2对于RP3V神经元中kisspeptin肽的青春期前发育至关重要，并提示在青春期前存在E2 - kisspeptin正反馈机制。这意味着在青春期前，RP3V kisspeptin神经元是GnRH神经元活动的E2依赖性放大器。
