Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest 1083, Hungary.
János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest 1085, Hungary.
Proc Natl Acad Sci U S A. 2022 Jul 5;119(27):e2113749119. doi: 10.1073/pnas.2113749119. Epub 2022 Jun 28.
Kisspeptin neurons in the mediobasal hypothalamus (MBH) are critical targets of ovarian estrogen feedback regulating mammalian fertility. To reveal molecular mechanisms underlying this signaling, we thoroughly characterized the estrogen-regulated transcriptome of kisspeptin cells from ovariectomized transgenic mice substituted with 17β-estradiol or vehicle. MBH kisspeptin neurons were harvested using laser-capture microdissection, pooled, and subjected to RNA sequencing. Estrogen treatment significantly (. < 0.05) up-regulated 1,190 and down-regulated 1,139 transcripts, including transcription factors, neuropeptides, ribosomal and mitochondrial proteins, ion channels, transporters, receptors, and regulatory RNAs. Reduced expression of the excitatory serotonin receptor-4 transcript () diminished kisspeptin neuron responsiveness to serotonergic stimulation. Many estrogen-regulated transcripts have been implicated in puberty/fertility disorders. Patients ( = 337) with congenital hypogonadotropic hypogonadism (CHH) showed enrichment of rare variants in putative CHH-candidate genes (e.g., , , ). Comprehensive characterization of the estrogen-dependent kisspeptin neuron transcriptome sheds light on the molecular mechanisms of ovary-brain communication and informs genetic research on human fertility disorders.
中脑基底部（MBH）的 kisspeptin 神经元是卵巢雌激素反馈调节哺乳动物生育能力的关键靶标。为了揭示这种信号转导的分子机制，我们使用激光捕获显微解剖术从用 17β-雌二醇或载体替代的卵巢切除转基因小鼠的 kisspeptin 细胞中彻底表征了雌激素调节的转录组。将 MBH kisspeptin 神经元收集并进行 RNA 测序。雌激素处理显着（<.05）上调了 1,190 个转录本和下调了 1,139 个转录本，包括转录因子、神经肽、核糖体和线粒体蛋白、离子通道、转运蛋白、受体和调节 RNA。兴奋性血清素受体-4 转录本（）的表达减少降低了 kisspeptin 神经元对 5-羟色胺刺激的反应性。许多雌激素调节的转录本与青春期/生育障碍有关。患有先天性低促性腺激素性性腺功能减退症（CHH）的患者（=337）在潜在的 CHH 候选基因（例如，）中显示出罕见变异的富集。对雌激素依赖性 kisspeptin 神经元转录组的全面表征揭示了卵巢-大脑通讯的分子机制，并为人类生育障碍的遗传研究提供了信息。
