P346 - ECE_3422 - Microglia rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis

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) neuron function. In addition, we identify rare gene variants of RANK in patients with HH. Transcriptional profiling upon Rank loss reveals 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 role of microglia in regulating GnRH neuronal function through Rank signaling, with implications for reproductive maturation and fertility.