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

  • Science. 2026 May 21;392(6800):eaeb6999. doi: 10.1126/science.aeb6999.
Alejandro Collado-Sole  1 ,  Nozha Borjini  2  3  4 ,  Jing Zhai  5  6 ,  Francisco Ruiz-Pino  7  8  9 ,  Gonzalo Soria-Alcaide  1 ,  Cintia Folgueira  10  11 ,  Celia García-Vilela  12 ,  Beatriz Romero-de la Rosa  7  8  9 ,  Victor Lopez  1 ,  Yassine Zouaghi  5  6  13 ,  An Jacobs  14 ,  Bella Mora-Romero  2  3  15 ,  Alexandra Barranco  1 ,  Guillermo Yoldi  16 ,  Karine Rizzoti  17  18 ,  Guadalupe Sabio  1  10 ,  Gema Perez-Chacon  1  19 ,  Patricia G Santamaria  1 ,  Jose Antonio Esteban  12 ,  Nathalie Journiac  20  21 ,  Vincent Prevot  20  21 ,  Alberto Pascual  2  3 ,  Rafael Fernández-Chacón  2  3  4 ,  Manuel Tena-Sempere  7  8  9 ,  Nelly Pitteloud  5  6 ,  Eva Gonzalez-Suarez  1  16
Affiliations
  • 1. Tumor Biology and Immunology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 2. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
  • 3. Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, Seville, Spain.
  • 4. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
  • 5. Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland.
  • 6. Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
  • 7. Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia, Córdoba, Spain.
  • 8. Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.
  • 9. CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Córdoba, Spain.
  • 10. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 11. Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.
  • 12. Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
  • 13. Department of Pediatrics, Stanford University, Stanford, CA, USA.
  • 14. Department of Medicine, Endocrinology, Diabetology, and Metabolism Unit, CHUV, Lausanne, Switzerland.
  • 15. Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla, Seville, Spain.
  • 16. Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain.
  • 17. Laboratory of Stem Cell Biology and Developmental Genetics, The Francis Crick Institute, London, UK.
  • 18. Centre for Endocrinology, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • 19. Tumor Microenvironment and Immunomodulation Unit, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
  • 20. Lille University, Inserm, CHU Lille, Lille Neuroscience and Cognition, UMR-S 1172, Labex DistAlz, Lille, France.
  • 21. Laboratory of Development and Plasticity of the Neuroendocrine Brain, FHU 1000 Days for Health, EGID, Lille, France.
PMID: 41818388 DOI: 10.1126/science.aeb6999
Abstract

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.

Products