Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis
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 <i>RANK</i> 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.
Authors
- Alberto Pascual (ORCID: https://orcid.org/0000-0001-5459-6207)
- Gema Pérez-Chacón (ORCID: https://orcid.org/0000-0002-2081-0882)
- Cintia Folgueira (ORCID: https://orcid.org/0000-0003-3803-9149)
- Celia García-Vilela
- Alejandro Collado-Solé (ORCID: https://orcid.org/0000-0001-7117-6896)
- José A. Esteban (ORCID: https://orcid.org/0000-0003-4250-9123)
- Nozha Borjini (ORCID: https://orcid.org/0000-0003-3729-2521)
- Nathalie Journiac (ORCID: https://orcid.org/0000-0001-6328-0802)
- Alexandra Barranco
- Karine Rizzoti (ORCID: https://orcid.org/0000-0003-0711-5452)
- Francisco Ruíz-Pino (ORCID: https://orcid.org/0000-0002-9217-8230)
- Gonzalo Soria-Alcaide (ORCID: https://orcid.org/0000-0001-5141-2177)
- Víctor López (ORCID: https://orcid.org/0000-0002-0395-995X)
- Manuel Tena-Sempere
- Jing Zhai
- An Jacobs
- Patricia G. Santamaria
- Bella Mora-Romero
- Guillermo Yoldi
- Yassine Zouaghi
- Guadalupe Sabio
- Beatriz Romero-de la Rosa
- Nelly Pitteloud
- Eva Gonzalez-Suarez
- Rafael Fernández-Chacón
- Vincent Prevot
Institutions
- Inserm (FR)
- Queen Mary University of London (GB)
- Université de Lille (FR)
- The Francis Crick Institute (GB)
- Instituto de Salud Carlos III (ES)
- Centre Hospitalier Universitaire Vaudois (CH)
- Spanish National Centre for Cardiovascular Research (ES)
- Centre Hospitalier Universitaire de Lille (FR)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Spanish National Cancer Research Centre (ES)
- Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
- Hôpital Orthopédique de la Suisse Romande (CH)
- Instituto de Biomedicina de Sevilla (ES)
- Centro de Biología Molecular Severo Ochoa (ES)
- Instituto de Investigación Sanitaria de Santiago (ES)
- William Harvey Research Institute (GB)
- Hospital Universitario Virgen del Rocío (ES)
- European Genomic Institute for Diabetes (FR)
- University of Córdoba (ES)
- Universidad Autónoma de Madrid (ES)
- Universidad de Sevilla (ES)
- Stanford University (US)
- University of Lausanne (CH)
Publication Details
- Journal
- Science
- Published
- 2026-03-12
- DOI
- https://doi.org/10.1126/science.aeb6999
- Primary Topic
- Hypothalamic control of reproductive hormones
- Type
- article
- Field-Weighted Citation Impact
- 0.00