Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis
Summary
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
Content
# Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis
*Published: 2026 May 21*
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.
DOI: 10.1126/science.aeb6999