Microglia Rank signaling regulates GnRH function and the Hypothalamic-Pituitary-Gonadal axis
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Alejandro Collado-Sole Nozha Borjini Jing Zhai Gonzalo Soria-Alcaide Cintia Folgueira Francisco Ruiz-Pino Celia Garcia Vilela 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 Alberto Pascual Bravo Rafael Fernández-Chacón Manuel Tena-Sempere Nelly Pitteloud Eva Gonzalez-SuarezThis article is a preprint. Preprints have not been peer-reviewed.
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Abstract
The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We hereby demonstrate a new role of hypothalamic microglia in controlling the HPG axis through Rank signaling, a pathway known for its role in bone and mammary gland biology. Whole-body and microglia Rank depletion leads to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) function. In addition, we identify rare gene variants of RANK in patients with HH. Transcriptional profiling upon pubertal Rank loss reveals defective microglia activation and morphological alterations in the median eminence (ME), decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH responses to kisspeptin. Overall, our data uncovers the crucial role of microglia in regulating GnRH function through Rank signaling, with implications for reproductive maturation and fertility.
One-Sentence Summary Microglia regulates GnRH function through RANK signaling
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bioRxiv
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