The kickoff signals for puberty begin in the brain. Specifically, in the hypothalamus, certain neurons release hormones that activate the pituitary gland at the base of the skull, which then releases other hormones to initiate maturation of the gonads (ovaries or testes). This mechanism leading to fertile organisms is the hypothalamic-pituitary-gonadal (HPG) axis.
Research by Spain’s National Cancer Research Center (CNIO) has discovered in animal models that two previously unsuspected elements are also involved in this hormonal regulatory system. microglia (defense cells of the nervous system) and RANK, a protein that contributes to bone remodeling and is essential for mammary gland function.
Article was published in a magazine science. The organization is led by Eva González Suárez, head of the CNIO Transformation and Metastasis Group, who discovered in 2010 the important role that RANK plays in the development of breast cancer. The first author is Alejandro Collado, a researcher in the same group and co-author.
Immune cells that regulate fertility
The hypothalamic-pituitary-gonadal axis regulates many processes related to reproduction. Its main role in the hypothalamus is as a gonadotropin-releasing neuron (GnRH). Gonadotropins are two hormones that control the onset of puberty, gonad development, and fertility. Although it has long been known that GnRH neurons are regulated by other neurons, it was not known that immune cells could influence their function.
This is a newly discovered function of microglia, cells in the central nervous system that eliminate potential threats and useless molecules.
It is important to find the cells that control fertility, which are immune cells rather than neurons. ”
Eva González Suárez, Head of Transformation and Transfer Group, CNIO
This study shows how microglia regulate GnRH neuron function. rank protein.
When the CNIO group suppressed RANK expression in animal models, reproductive function was distorted in both males and females. In individuals born without RANK, Alternatively, if it was removed in prepubertal animals, a decrease in sex hormones and a loss of gonadal function known as hypogonadism occurred, and puberty did not occur in these animals. When RANK was removed from sexually mature specimens, they became sterile within a month.
New mutations in human syndromes
To investigate whether RANK may play a role in human fertility, researchers genetically analyzed samples taken from patients with congenital hypogonadotropin, a rare syndrome associated with delayed or absent puberty and infertility. This was known to be caused by problems with GnRH neurons or the molecules they produce. The study identified mutations in the gene encoding the RANK protein in some patients..
According to the authors, “These results demonstrate that RANK may be a potential therapeutic target for endocrine diseases and syndromes that affect fertility, as well as a candidate gene for the molecular diagnosis of congenital hypogonadotropic hypogonadism.”
González-Suárez emphasizes that “the role of microglia in regulating the function of ‘reproductive’ neurons is novel, and this regulation associated with RANK can also occur in other functional axes, such as the appetite-satiety axis or the stress axis.”
The importance of collaboration
The authors also wish to highlight this study as an example of the importance of interdisciplinary collaboration. “My doctoral thesis began with the question of whether the RANK protein plays a role in the development of mammary tissue in the breast itself during adolescence,” Corrado explains. “When we realized we needed to investigate questions that had implications for fertility, neurons, and brain cells, we started consulting colleagues in other fields.”
The team therefore began a collaboration with Manuel Tena Sempere from the University of Córdoba and the Maimonides Biomedical Institute (IMIBIC) in Córdoba, Vincent Prévost from Inserm (French National Institute for Health and Medical Research), Rafael Fernández Chacón from the Institute of Biomedical Research in Seville (IBiS), and Nellie Pitrude from the Center Hospitalier. University of Vaudois (CHUV), Switzerland.
“We reached unforeseen conclusions and learned techniques and tools that we can apply to future research,” Collard said.
sauce:
National Cancer Institute (CNIO)
Reference magazines:
Corrado Sole, A. others. (2026) Microglial rank signaling regulates GnRH neuron function and the hypothalamic-pituitary-gonadal axis. science. DOI: 10.1126/science.aeb6999. https://www.science.org/doi/10.1126/science.aeb6999
