Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis

• 成果类型: Article
• 署名作者: Collado-Sole, Alejandro; Borjini, Nozha; Zhai, Jing; Ruiz-Pino, Francisco; Soria-Alcaide, Gonzalo; Folgueira, Cintia; Garcia-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; Fernandez-Chacon, Rafael; Tena-Sempere, Manuel; Pitteloud, Nelly; Gonzalez-Suarez, Eva
• 署名单位: Centro Nacional de Investigaciones Oncologicas (CNIO); Consejo Superior de Investigaciones Cientificas (CSIC); University of Sevilla; Virgen del Rocio University Hospital; CSIC-JA-USE - Instituto de Biomedicina de Sevilla (IBIS); University of Sevilla; CIBERNED; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Lausanne; Hospital Universitario Reina Sofia - Cordoba; Universidad de Cordoba; CIBER - Centro de Investigacion Biomedica en Red; Instituto de Salud Carlos III; CIBEROBN; Centro Nacional de Investigaciones Cardiovasculares (CNIC); Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de Biologia Molecular Severo Ochoa (CBM); Stanford University; Stanford Medicine; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Sevilla; University of Barcelona; Institut d'Investigacio Biomedica de Bellvitge (IDIBELL); Francis Crick Institute; University of London; Queen Mary University London; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Lille; CHU Lille; Universite de Lille
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aeb6999
• 发表日期: 2026-05-21
• 页码: eaeb6999
• 关键词: CONGENITAL HYPOGONADOTROPIC HYPOGONADISM; LUTEINIZING-HORMONE SECRETION; MAMMARY-GLAND; gene-expression; estrogen; GONADOTROPIN; receptor; differentiation; reproduction; mechanisms

摘要

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 kappa B (Rank) signaling. Whole-body and microglia Rank (mouse) 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 RANK (human) 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.