Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis
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Alejandro Collado-Sole Nozha Borjini Jing Zhai Francisco Ruiz-Pino Gonzalo Soria-Alcaide Cintia Folgueira Celia García-Vilela Beatriz Romero-de la Rosa Victor Lopez Yassine Zouaghi An Jacobs Bella Mora-Romero Alexandra Barranco Guillermo Yoldi Karine Rizzoti Guadalupe Sabio Gema Perez-Chacon Patricia G Santamaria Jose Antonio Esteban Nathalie Journiac Vincent Prevot Alberto Pascual Rafael Fernández-Chacón Manuel Tena-Sempere Nelly Pitteloud Eva Gonzalez-Suarez
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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 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 RANK 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.
Journal details
Journal
Science
Volume
392
Issue number
6800
Pages
aeb6999
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10.1126/science.aeb6999
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Europe PubMed Central
41818388
Pubmed
41818388
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The publication was previously a preprint.
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