Alejandro Collado-Solé, Nozha Borjini, Jing Zhai, Francisco Ruíz-Pino, Gonzalo Soria-Alcaide, Cintia Folgueira, Celia García-Vilela, Beatriz Romero-de la Rosa, Víctor López, Yassine Zouaghi, An Jacobs, Bella Mora-Romero, Alexandra Barranco, Guillermo Yoldi, Karine Rizzoti, Guadalupe Sabio, Gema Pérez-Chacón, Patricia G. Santamaria, José A. Esteban, Nathalie Journiac, Vincent Prévot, Alberto Pascual, Rafael Fernández-Chacón, Manuel Tena-Sempere, Nelly Pitteloud, Eva Gonzalez-Suarez
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 κB (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.