Clarkson Jenny, d'Anglemont de Tassigny Xavier, Moreno Adriana Santos, Colledge William H, Herbison Allan E
Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Medical Sciences, Dunedin 9054, New Zealand.
J Neurosci. 2008 Aug 27;28(35):8691-7. doi: 10.1523/JNEUROSCI.1775-08.2008.
Kisspeptin and its receptor GPR54 have recently been identified as key signaling partners in the neural control of fertility in animal models and humans. The gonadotropin-releasing hormone (GnRH) neurons represent the final output neurons of the neural network controlling fertility and are suspected to be the primary locus of kisspeptin-GPR54 signaling. Using mouse models, the present study addressed whether kisspeptin and GPR54 have a key role in the activation of GnRH neurons to generate the luteinizing hormone (LH) surge responsible for ovulation. Dual-label immunocytochemistry experiments showed that 40-60% of kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) expressed estrogen receptor alpha and progesterone receptors. Using an ovariectomized, gonadal steroid-replacement regimen, which reliably generates an LH surge, approximately 30% of RP3V kisspeptin neurons were found to express c-FOS in surging mice compared with 0% in nonsurging controls. A strong correlation was found between the percentage of c-FOS-positive kisspeptin neurons and the percentage of c-FOS-positive GnRH neurons. To evaluate whether kisspeptin and/or GPR54 were essential for GnRH neuron activation and the LH surge, Gpr54- and Kiss1-null mice were examined. Whereas wild-type littermates all exhibited LH surges and c-FOS in approximately 50% of their GnRH neurons, none of the mutant mice from either line showed an LH surge or any GnRH neurons with c-FOS. These observations provide the first evidence that kisspeptin-GPR54 signaling is essential for GnRH neuron activation that initiates ovulation. This broadens considerably the potential roles and therapeutic possibilities for kisspeptin and GPR54 in fertility regulation.
亲吻素及其受体GPR54最近已被确定为动物模型和人类生育神经控制中的关键信号传导伙伴。促性腺激素释放激素（GnRH）神经元代表控制生育的神经网络的最终输出神经元，并且被怀疑是亲吻素 - GPR54信号传导的主要位点。本研究使用小鼠模型探讨了亲吻素和GPR54在激活GnRH神经元以产生负责排卵的促黄体生成素（LH）激增中是否起关键作用。双标记免疫细胞化学实验表明，第三脑室室周区前部（RP3V）中40 - 60%的亲吻素神经元表达雌激素受体α和孕激素受体。使用去卵巢、性腺类固醇替代方案，该方案可可靠地产生LH激增，与未出现激增的对照组中0%相比，在出现激增的小鼠中发现约30%的RP3V亲吻素神经元表达c-FOS。发现c-FOS阳性亲吻素神经元的百分比与c-FOS阳性GnRH神经元的百分比之间存在强相关性。为了评估亲吻素和/或GPR54对于GnRH神经元激活和LH激增是否必不可少，对Gpr54基因敲除和Kiss1基因敲除小鼠进行了检查。野生型同窝小鼠的GnRH神经元中约50%均表现出LH激增和c-FOS，而这两个品系的突变小鼠均未出现LH激增或任何带有c-FOS的GnRH神经元。这些观察结果提供了首个证据，表明亲吻素 - GPR54信号传导对于启动排卵的GnRH神经元激活至关重要。这极大地拓宽了亲吻素和GPR54在生育调节中的潜在作用和治疗可能性。
