Microglia Rank signaling regulates GnRH function and the Hypothalamic-Pituitary-Gonadal axis

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; Eva Gonzalez-Suarez

doi:10.64898/2026.02.18.706528

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Microglia Rank signaling regulates GnRH function and the Hypothalamic-Pituitary-Gonadal axis

Alejandro Collado-Sole, Nozha Borjini, Jing Zhai +20 more

February 2026

bioRxiv

DOI

10.64898/2026.02.18.706528

Reproducible

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This paper passed independent validation.

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It ranks in the top 1% of preprints assessed in Cell Biology this quarter.

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Why this is interesting

Demonstrating that hypothalamic microglia govern GnRH neuron function via RANK signaling—engulfing GnRH terminals and controlling kisspeptin responses—this work redefines microglia as essential neuroendocrine regulators and connects a bone-immune pathway to human infertility.

Author perspective

What is the most innovative aspect of your work?

“

One of the most innovative findings is that microglia control GnRH neurons, which control fertility. It had previously been described that microglia can control some neuronal aspects, but this description for this kind of neuron was not defined until the paper's results.

”

Alejandro Collado-Sole

QED claims analysis

Summary

Hypothalamic microglia regulate gonadotropin-releasing hormone (GnRH) function and the hypothalamic-pituitary-gonadal axis through RANK signaling, where microglia-specific RANK loss reduces microglia-GnRH terminal contacts in the median eminence, impairs GnRH responsiveness to kisspeptin, and causes hypogonadotropic hypogonadism in mice, with rare RANK gene variants identified in human patients with congenital hypogonadotropic hypogonadism.

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Main Claim 1 –

Whole-body Rank deletion causes hypogonadotropic hypogonadism in mice

Supporting evidence

GnRH-neuron Rank deletion does not disrupt HPG axis establishment
Rank loss impairs GnRH responsiveness to kisspeptin stimulation

Main Claim 2 –

Postnatal Rank deletion suppresses male HPG axis and fertility

Supporting evidence

Pubertal inducible microglial Rank deletion impairs HPG axis function

Main Claim 3 –

Rare RANK variants are found in congenital hypogonadotropic hypogonadism

Main Claim 4 –

Hypothalamic Rank is microglia-enriched and regulates the HPG axis

Supporting evidence

Microglia-specific Rank deletion induces hypogonadotropic hypogonadism
Peripheral myeloid Rank loss does not affect fertility or maturation
Rank loss reduces hypothalamic microglia activation and phagocytic programs
Rank loss selectively alters microglia morphology in the median eminence
Microglial Rank loss reduces GnRH contacts and phagocytosis in median eminence

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.

Microglia regulates GnRH function through RANK signaling

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Physiology

Animal Behavior and Cognition

Developmental Biology

Microbiology