Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Institute of Acupuncture and Moxibustion Research, Academy of Integrative Medicine, Fudan University, Shanghai, China.
Shanghai Dunlu Biomedical Technology Co., Ltd, Shanghai, China.
Biol Reprod. 2019 Jun 1;100(6):1536-1548. doi: 10.1093/biolre/ioz044.
Precocious puberty (PP) commonly results from premature activation of the hypothalamic-pituitary-gonadal axis (HPGA). Gonadotropin-releasing hormone (GnRH) is the initial trigger for HPGA activation and plays an important role in puberty onset. N-methyl-D-aspartate (NMDA) can promote pulsatile GnRH secretion and accelerates puberty onset. However, the mechanism of N-methyl-D-aspartate receptors (NMDARs) in PP pathogenesis remains obscure. We found that serum GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen (E2) levels, hypothalamic NMDAR1, and GnRH mRNA expression peaked at the vaginal opening (VO) day. Next, the hypothalamic NMDAR1 mRNA and protein levels in rats treated with danazol, a chemical commonly effecting on the reproductive system, were significantly increased at the VO day (postnatal day 24) compared to controls, accompanied by enhanced serum GnRH, LH, FSH, and E2 levels. Further, microRNA-664-2 (miR-664-2) was selected after bioinformatics analysis and approved in primary hypothalamic neurons, which binds to the 3'-untranslated regions of NMDAR1. Consistently, the miR-664-2 expression in hypothalamus of the Danazol group was decreased compared to Vehicle. Our results suggested that attenuated miR-664-2 might participate in PP pathogenesis through enhancing the NMDAR1 signaling.
性早熟（PP）通常是由于下丘脑-垂体-性腺轴（HPGA）过早激活引起的。促性腺激素释放激素（GnRH）是 HPGA 激活的初始触发因素，在青春期开始中发挥重要作用。N-甲基-D-天冬氨酸（NMDA）可以促进 GnRH 的脉冲式分泌，从而加速青春期的开始。然而，NMDA 受体（NMDARs）在 PP 发病机制中的作用机制仍不清楚。我们发现，血清 GnRH、黄体生成素（LH）、卵泡刺激素（FSH）、雌激素（E2）水平、下丘脑 NMDAR1 和 GnRH mRNA 表达在阴道开口（VO）日达到峰值。接下来，用丹那唑（一种常用于生殖系统的化学物质）处理的大鼠下丘脑 NMDAR1 mRNA 和蛋白水平在 VO 日（出生后第 24 天）明显高于对照组，同时血清 GnRH、LH、FSH 和 E2 水平也升高。此外，经过生物信息学分析后选择了 microRNA-664-2（miR-664-2），并在原代下丘脑神经元中得到了验证，该 miRNA 可与 NMDAR1 的 3'-非翻译区结合。一致的是，与 Vehicle 相比，丹那唑组下丘脑的 miR-664-2 表达降低。我们的结果表明，减弱的 miR-664-2 可能通过增强 NMDAR1 信号参与 PP 的发病机制。
