Brain's Defense Cells May Control The Onset of Puberty

Researchers have discovered that immune cells in the brain called microglia help control the onset of puberty and fertility. These cells use a protein called RANK to communicate with neurons that activate the reproductive hormonal system. When this protein doesn't function correctly, the process that initiates puberty can fail, leading to low levels of sex hormones and infertility.

For a long time, scientists believed that the onset of puberty was controlled only by neurons, the brain cells responsible for transmitting electrical and chemical signals. However, a new study has revealed something surprising: immune system cells that live inside the brain also participate in this process. This discovery shows that human fertility depends on a much more complex cooperation between different types of cells than previously thought.

The onset of puberty begins in a small region of the brain called the hypothalamus, which functions as a control center for various bodily functions, such as temperature, hunger, and hormones. In this area, specialized neurons release a chemical that sends signals to another gland located at the base of the brain, called the pituitary gland.

The pituitary gland, in turn, releases hormones into the bloodstream that stimulate the ovaries or testicles, initiating sexual development and the production of hormones such as estrogen and testosterone. This communication system between the brain and reproductive organs functions as a chain of messages that coordinates growth and fertility.

Researchers have discovered that, in addition to neurons, another type of cell also participates in this system: microglia. These cells are part of the brain's defense system. They patrol nervous tissue in search of threats, such as infections or damaged cells, and also help to "clean up" debris and reorganize connections between neurons.

Until recently, it was believed that microglia only protected the brain, but the new study showed that they also help regulate important hormonal functions.

The functioning of this regulation involves a protein called RANK. Proteins are molecules that perform various functions within cells, often acting as switches or messengers.

Scientists observed that microglia use this protein to communicate with neurons responsible for initiating the reproductive process. When researchers removed this protein in experiments with mice, the hormonal system stopped functioning correctly: sex hormone levels dropped, reproductive organs did not develop normally, and the animals did not go through puberty.

Microglia

To understand how this happens, scientists analyzed the brains of animals using gene study techniques and advanced microscopy. They observed that, without the RANK protein, microglia cells did not function correctly. This altered the structure of a brain region where neurons that control reproduction release their signals.

Normally, microglia help reorganize small extensions of neurons, a process comparable to pruning branches on a tree so that it grows better. Without this "maintenance," neurons cannot respond adequately to the chemical signals that activate the onset of puberty.

The researchers also investigated whether this mechanism could exist in humans. To do this, they analyzed the genetic material of patients with a rare condition in which puberty does not occur or occurs very late. This problem is associated with infertility and very low levels of sex hormones.

In some of these patients, scientists found alterations in the gene responsible for producing the RANK protein, suggesting that the same mechanism discovered in animals may also occur in humans.

This discovery opens new possibilities for understanding fertility problems and hormonal disorders. Furthermore, scientists suspect that the brain's immune cells may influence other body systems that also depend on hormonal signals, such as those that regulate stress, appetite, and satiety. This means that the brain's immune system may play a much broader role in regulating the body than previously thought.

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Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis

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. 12 Mar 2026

DOI:10.1126/science.aeb6999

Abstract:

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.