Summary: In a surprising shift in our understanding of reproductive biology, researchers have discovered that fertility is not controlled by neurons alone. The study reveals that microglia—the brain’s primary immune defense cells—play a direct and essential role in sexual maturation and fertility.
By expressing a protein called RANK, these immune cells regulate the activity of GnRH neurons, the master controllers of puberty and reproduction. Without this immune-brain communication, the onset of puberty fails, and adult fertility is lost. This discovery opens new doors for treating endocrine disorders and rare infertility syndromes in humans.
Key Facts
- Beyond Neurons: While it was known that neurons modulate reproductive signals, this is the first evidence that immune cells (microglia) are a core component of the fertility regulatory system.
- The RANK Link: Microglia influence reproductive neurons by expressing the RANK protein. When RANK was removed from mice, puberty did not occur, sex hormones plummeted, and specimens remained infertile.
- Reversibility in Adults: In sexually mature mice, removing the RANK protein from microglia caused infertility within just one month, proving the system is required for ongoing reproductive health.
- Human Connection: The team identified genetic mutations in the RANK gene in patients with congenital hypogonadotropic hypogonadism, a rare syndrome causing absent puberty and infertility.
- Potential for Other Axes: Researchers suspect this immune-cell regulation may also exist in other brain systems, such as those controlling stress, appetite, and satiety.
Source: CNIO
The kick off signal for puberty begins in the brain. Specifically, in the hypothalamus, where specific neurons release a hormone that activates the hypophysis, at the base of the skull, which then releases other hormones to start gonad –ovaries or testicles –maturation. This mechanism leading to a fertile organism is the hypothalamic-pituitary-gonadal (HPG) axis.
A study by Spain’s National Cancer Research Centre (CNIO) has just discovered in animal models that two previously unsuspected elements are also involved in this hormone regulating system: microglia – defensive cells of the nervous system – and the protein RANK, which contributes to bone remodelling and is essential in the functioning of the mammary glands.
The article is published in the journal Science. It is led by Eva González-Suárez, head of the CNIO Transformation and Metastasis Group, who discovered in 2010 the key role played by RANK in the development of breast cancer. The first author is Alejandro Collado, a researcher from the same group and co- corresponding author.
Immune cells to modulate fertility
The hypothalamic-pituitary-gonadal axis regulates many processes related to reproduction. Its main players in the hypothalamus are gonadotropin-releasing neurons (GnRH). Gonadotropins are two hormones that control the onset of puberty, the development of the gonads, and fertility. It was previously known that GnRH neurons are modulated by other neurons, but not that immune cells could influence their functioning.
This is the newly discovered function of microglia, cells in the central nervous system that eliminate potential threats and molecules that serve no purpose. “Finding fertility-regulating cells that are not neurons, but rather immune cells, is important,” highlights González-Suárez.
The study shows that the way microglia regulate the function of GnRH neurons is by expressing the RANK protein.
When the CNIO group suppressed RANK expression in animal models, the reproductive function became distorted, both in males and females. In specimens born without RANK, or when it was removed in prepubescent animals, there was a reduction in sex hormones and a loss of gonad functionality known as hypogonadism, and puberty did not occur in these animals. When RANK was eliminated in sexually mature specimens, they became infertile within a month.
New mutations for a human syndrome
To investigate whether RANK might play a role in human fertility, researchers genetically analysed samples from patients with congenital hypogonadotropic hypogonadism, a rare syndrome associated with delayed or absent puberty and infertility. It was known that it is caused by problems in GnRH neurons or in the molecules they produce. The research 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, as well as a candidate gene for the molecular diagnosis of congenital hypogonadotropic hypogonadism,” according to the authors.
González-Suárez emphasises that “the role of microglia in regulating 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, the stress axis, etc.”
The importance of collaboration
The authors also want to highlight this research as an example of the importance of interdisciplinary collaboration.
“My doctoral thesis started out with the question of whether the RANK protein played any role in the development of mammary tissue, in the breast itself, during puberty,” Collado explains. “When we realised that we needed to explore issues implying fertility, neurons and brain cells, we started consulting colleagues from other fields.”
Thus the team began collaborating with Manuel Tena-Sempere, from
the University of Córdoba and the Maimónides Biomedical Research Institute in Córdoba (IMIBIC), Vincent Prevot from Inserm (France’s National Institute of Health and Medical Research), Rafael Fernández Chacón from the Biomedicine Institute (IBiS) in Seville, and Nelly Pitteleoud from the Centre Hospitalier Universitaire Vaudois (CHUV) in Switzerland.
“We have reached conclusions that we could not have foreseen and learned techniques and tools that we will now be able to apply to future studies,” Collado states.
Funding entities
European Research Council (ERC), “la Caixa” Foundation, Community of Madrid, and Ministry of Science, Innovation and Universities through the State Research.
Key Questions Answered:
A: Think of microglia as the “quality control” and “maintenance crew” of the brain. We used to think they just cleaned up debris, but this study shows they actually help “flip the switch” for puberty. They monitor the environment and talk to the reproductive neurons, ensuring the body’s internal conditions are right for maturation.
A: Yes. By finding mutations in the RANK gene in patients with rare infertility syndromes, scientists have identified a new target for therapy. It means we might be able to treat certain fertility issues by targeting the brain’s immune cells rather than just focusing on hormones or the reproductive organs themselves.
A: Increasingly, the answer looks like a “yes.” This research bridges the gap between the immune system and the endocrine system. If microglia are the “gatekeepers” for reproductive hormones, then factors that stress the brain’s immune system—like chronic inflammation—could theoretically impact hormonal balance.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuroscience and fertility research news
Author: Mónica González
Source: CNIO
Contact: Mónica González – CNIO
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis” by 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 Zouaghi, An Jacobs, 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. 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 (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 κβ (Rank) signaling.
Whole-body and microglia Rank 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 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.
