Linking fertility with immune cells in the brain
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 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.
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 an author.
The study shows that the way microglia regulate the function of GnRH neurons is by expressing the RANK protein.
When the 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.
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.
The author 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."
https://www.science.org/doi/10.1126/science.aeb6999
