Microglia and RANK Signaling: Fresh Insights into Puberty and Fertility

Researchers at the Spanish National Cancer Research Center (CNIO) have discovered a surprising link between immune cells in the brain, the RANK protein, and the onset of puberty, and fertility. The study, published in Science on March 12, 2026, reveals that microglia, the brain’s resident immune cells, regulate reproductive function through the expression of the RANK protein. This finding not only sheds light on the complex hormonal regulation of puberty but also identifies potential therapeutic targets for infertility and related endocrine disorders.

The Hypothalamic-Pituitary-Gonadal Axis and the Role of Microglia

The process of sexual maturation is orchestrated by the hypothalamic-pituitary-gonadal (HPG) axis. This system begins in the hypothalamus, which releases hormones that activate the pituitary gland, ultimately triggering the maturation of the ovaries or testicles. Traditionally, this axis was understood to be regulated by neurons, but this research demonstrates a previously unknown role for immune cells.

The CNIO study shows that microglia, which typically eliminate threats and waste in the central nervous system, influence the function of gonadotropin hormone-releasing neurons (GnRH) – key players in the HPG axis – through the expression of the RANK protein. “The fact of finding cells that are not neurons, but immune cells, regulating fertility is already important,” highlights Eva González-Suárez, head of the Transformation and Metastasis Group at CNIO.

RANK Protein: A Key Regulator of Reproductive Function

Experiments in animal models revealed that suppressing the expression of the RANK protein disrupted reproductive function in both males and females. Animals lacking RANK exhibited reduced sex hormone levels and impaired gonadal function, failing to undergo puberty. In sexually mature animals, removing RANK led to infertility within a month.

Implications for Human Fertility and Congenital Hypogonadotropic Hypogonadism

To investigate the relevance of these findings to human health, the researchers analyzed samples from patients with congenital hypogonadotropic hypogonadism (CHH), a rare syndrome characterized by delayed or absent puberty and infertility. They identified mutations in the gene encoding the RANK protein in some patients.

“These results show that RANK could be a therapeutic target for endocrine disorders and syndromes affecting fertility, and also a candidate gene for the molecular diagnosis of congenital hypogonadotrophic hypogonadism,” the authors write.

Expanding the Scope: Potential Links to Other Brain Functions

González-Suárez suggests that the role of microglia in regulating neuronal function extends beyond reproduction. “The role of microglia as a regulator of the function of ‘reproductive’ neurons is new, and this regulation associated with RANK can occur in other axes, for other functions, such as the appetite-satiety axis, stress, etc.”

The Importance of Interdisciplinary Collaboration

The success of this research underscores the value of collaboration across scientific disciplines. The CNIO team worked with researchers from the University of Córdoba, Inserm (France), the Institute of Biomedicine of Seville, and the Center Hospitalier Universitaire Vaudois (Switzerland) to integrate expertise in immunology, neuroscience, and endocrinology.

Funding and Research Center Information

This research was funded by the European Research Council (ERC), «la Caixa» Foundation, the Autonomous Community of Madrid, and the Ministry of Science and Innovation through the State Research Agency, co-financed by the European Regional Development Fund (ERDF).

The National Cancer Research Center (CNIO) is a leading public research center in Spain dedicated to improving the prevention, diagnosis, and treatment of cancer.

Reference: Alejandro Collado-Sole, Nozha Borjini, Jing Zhai, Francisco Ruiz-Pino, Gonzalo Soria-Alcaide, Cintia Folgueira, Celia García-Vilela, Beatriz Romero-de la Rosa, Victor Lopez, Yassine Zouaghi5, An Jacob, Bella Mora-Romero, Alexandra Barranco, Guillermo Yoldi, Karine Rizzoti, Guadalupe Sabio, Gema Perez-Chacon, Patricia G. Santamaria, Jose Antonio Esteban, Nathalie Journiac, Vincent Prevot, Alberto Pascual, Rafael Fernández-Chacón, Manuel Tena-Sempere, Nelly Pitteloud and Eva Gonzalez-Suarez, Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis, Science, 2026. DOI: 10.1126/science.aeb6999