Summary: Researchers have uncovered a surprising new regulator of reproductive development: microglia, the brain’s resident immune cells. The study shows that microglia influence the neurons that trigger puberty and maintain fertility by expressing the RANK protein. Disruption of this immune–brain signaling prevents puberty and causes infertility in animal models, and mutations in the RANK gene were identified in human patients with congenital hypogonadotropic hypogonadism. These findings point to new diagnostic and therapeutic avenues for endocrine disorders and infertility.
The research demonstrates that fertility is not governed solely by neuronal circuits. Microglia communicate directly with gonadotropin-releasing hormone (GnRH) neurons, which sit at the top of the hypothalamic-pituitary-gonadal (HPG) axis and control the hormonal cascade that drives gonad maturation and reproductive function. By expressing receptor activator of nuclear factor κB (RANK), microglia shape GnRH neuron activity and, consequently, the onset of puberty and ongoing fertility.
Key Facts
- Immune cells as core regulators: Beyond their known roles in immune surveillance and debris clearance, microglia are shown to be essential components of the reproductive regulatory network.
- RANK is central: Microglial expression of the RANK protein is required for normal GnRH neuron function. Loss of RANK in animal models prevented puberty, drastically lowered sex hormones, and caused infertility.
- Necessary in adults and juveniles: Deleting RANK from microglia in sexually mature animals caused infertility within weeks, indicating this signaling pathway is required continuously, not only during development.
- Human relevance: Genetic analysis of patients with congenital hypogonadotropic hypogonadism revealed rare RANK gene variants, linking the mechanism to a human syndrome characterized by absent or delayed puberty and infertility.
- Broader implications: The authors suggest similar microglia-mediated regulation could exist across other hypothalamic axes, including those that control stress responses, appetite, and satiety.
Source: CNIO
How the puberty signal is generated
Puberty and reproductive maturation are initiated by a hormonal cascade originating in the hypothalamus. Specialized neurons there release gonadotropin-releasing hormone (GnRH), which prompts the pituitary gland to secrete gonadotropins. Those pituitary hormones then stimulate the gonads—ovaries or testes—to mature and produce sex steroids. This coordinated process is known as the hypothalamic-pituitary-gonadal (HPG) axis.
A team at Spain’s National Cancer Research Centre (CNIO) found that, in animal models, microglia and the protein RANK are integral to HPG axis regulation. Microglia, traditionally viewed as the brain’s defensive cells, were discovered to influence GnRH neurons through RANK signaling, a pathway previously studied in bone remodeling and mammary gland biology.
The findings appear in the journal Science and were led by Eva González-Suárez, head of the CNIO Transformation and Metastasis Group, with Alejandro Collado as first author and co-corresponding author. González-Suárez previously described RANK’s role in breast cancer development in 2010.
Immune cells modulate fertility
GnRH neurons are the central neuronal drivers of puberty and fertility, and until now researchers had focused on how other neurons and molecular signals regulate them. This study adds a new dimension: microglia physically interact with GnRH neuron projections in the hypothalamus and modulate their function via RANK signaling. When RANK expression was removed from microglia in animal models—either from birth or during prepubertal development—the animals developed hypogonadotropic hypogonadism: low gonadotropin levels, reduced sex steroids, dysfunctional gonads, and failure to undergo puberty. Deleting RANK in adult animals rapidly led to infertility, underscoring the pathway’s ongoing importance.
New RANK mutations linked to a human syndrome
To test whether these mechanisms are relevant to humans, the team analyzed DNA from patients with congenital hypogonadotropic hypogonadism (CHH), a rare condition marked by absent or delayed puberty and infertility. The study identified rare variants in the RANK gene in some CHH patients, supporting a role for microglial RANK signaling in human reproductive disorders. The authors note that RANK could therefore be both a diagnostic candidate gene and a therapeutic target for certain forms of hypogonadism and infertility.
The research further found that loss of RANK altered microglial activation and the structure of the median eminence—a hypothalamic region important for neuroendocrine communication—reducing microglial contact and engulfment of GnRH terminals and impairing GnRH neuron responses to the key puberty trigger, kisspeptin.
The importance of collaboration
The CNIO team emphasizes that answering this question required interdisciplinary collaboration across neuroscience, endocrinology, genetics, and molecular biology. Alejandro Collado explains that the project began with questions about RANK in mammary development and expanded to include specialists in brain and reproductive biology as the data pointed toward a neural mechanism. Collaborators included researchers from the University of Córdoba, the Maimónides Biomedical Research Institute (IMIBIC), Inserm (France), the Biomedicine Institute (IBiS) in Seville, and clinical partners in Switzerland.
These collaborations enabled the team to combine genetic analysis of human patients with mechanistic animal studies, advanced imaging, and transcriptional profiling to reveal how microglial RANK signaling shapes GnRH neuron function.
Funding entities: European Research Council (ERC), la Caixa Foundation, Community of Madrid, and the Spanish Ministry of Science, Innovation and Universities through state research programs.
Key Questions Answered
A: Microglia act as the brain’s maintenance and quality-control cells. Beyond clearing debris, they monitor the neuronal environment and interact directly with GnRH neuron projections. Through RANK signaling, they help determine whether conditions are suitable for initiating and maintaining the reproductive hormone cascade that triggers puberty and supports fertility.
A: Potentially yes. Identifying RANK variants in patients with congenital hypogonadotropic hypogonadism suggests new diagnostic markers and therapeutic targets. Interventions aimed at modulating microglial RANK signaling may complement traditional hormone-based treatments for certain forms of infertility.
A: Growing evidence, including this study, supports links between immune signaling in the brain and endocrine function. If microglia are key gatekeepers for reproductive hormone release, then chronic neuroinflammation or other disruptions to microglial function could plausibly impact hormonal regulation.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full by the editorial team.
- Additional contextual information was added by staff to clarify implications.
About this neuroscience and fertility research news
Author: Mónica González
Source: CNIO
Contact: Mónica González – CNIO
Image: Image credit: Neuroscience News
Original Research: Closed access. “Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis” by Alejandro Collado-Sole et al., Science. DOI: 10.1126/science.aeb6999
Abstract
Microglia RANK signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis
The hypothalamic-pituitary-gonadal axis 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-specific RANK depletion produced hypogonadotropic hypogonadism due to altered GnRH neuron function. Rare RANK variants were also found in patients with hypogonadotropic hypogonadism. Transcriptional profiling following RANK loss revealed impaired microglial activation and morphological changes in the median eminence that reduced microglial contact with and engulfment of GnRH terminals, and impaired GnRH neuronal responses to kisspeptin. These data position microglia as regulators of GnRH neuronal function via RANK signaling, with implications for reproductive maturation and fertility.