Collado-Sole Alejandro, Borjini Nozha, Zhai Jing, Ruiz-Pino Francisco, Soria-Alcaide Gonzalo, Folgueira Cintia, García-Vilela Celia, Romero-de la Rosa Beatriz, Lopez Victor, Zouaghi Yassine, Jacobs An, Mora-Romero Bella, Barranco Alexandra, Yoldi Guillermo, Rizzoti Karine, Sabio Guadalupe, Perez-Chacon Gema, Santamaria Patricia G, Esteban Jose Antonio, Journiac Nathalie, Prevot Vincent, Pascual Alberto, Fernández-Chacón Rafael, Tena-Sempere Manuel, Pitteloud Nelly, Gonzalez-Suarez Eva
Tumor Biology and Immunology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
Science. 2026 Mar 12:eaeb6999. doi: 10.1126/science.aeb6999.
The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We identified a role of hypothalamic microglia in controlling the HPG axis through receptor activator of nuclear factor κβ (Rank) signaling. Whole-body and microglia Rank depletion led to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) neuron function. In addition, we identified rare gene variants of in patients with HH. Transcriptional profiling upon Rank loss revealed defective microglia activation and morphological alterations in the median eminence, decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH neuronal responses to kisspeptin. Overall, our data uncover the microglia as regulator of GnRH neuronal function through Rank signaling, with potential implications for reproductive maturation and fertility.
下丘脑-垂体-性腺轴（HPG）控制青春期发育、性成熟和生育能力。我们发现下丘脑小胶质细胞通过核因子κβ受体激活剂（Rank）信号传导在控制HPG轴中发挥作用。全身和小胶质细胞Rank缺失导致促性腺激素释放激素（GnRH）神经元功能改变引起的低促性腺激素性性腺功能减退（HH）。此外，我们在HH患者中鉴定出罕见的基因变异。Rank缺失后的转录谱分析显示小胶质细胞激活缺陷和正中隆起的形态改变，减少了GnRH终末投射的接触和吞噬，并损害了GnRH神经元对亲吻素的反应。总体而言，我们的数据揭示小胶质细胞是通过Rank信号传导调节GnRH神经元功能的调节因子，对生殖成熟和生育能力具有潜在影响。
