Brain's immune cells linked to fertility

Immune cells within the brain emerge as regulators of puberty onset, maturation of reproductive organs and fertility.

The hypothalamic-pituitary-gonadal (HPG) axis is an endocrine system that controls reproductive function and sexual development. It includes a brain structure, the hypothalamus, which contains the gonadotropin-releasing hormone (GnRH) neurons that dictate the release of reproductive hormones by dedicated body glands. New research published in Science has now revealed that microglia, a type of resident brain cell involved in immune responses, also helps regulate the HPG axis and the function of GnRH neurons in mice via a protein called Rank. Crucially, mutations in the gene coding for RANK (the human version of Rank) were also found in people with congenital hypogonadotropic hypogonadism (HH), a syndrome associated with delayed or absent puberty and infertility.

'Finding fertility-regulating cells that are not neurons, but rather immune cells, is important' said Dr Eva González-Suárez, leader of the Transformation and Metastasis Group at the Spanish National Cancer Research Centre, adding that 'the role of microglia in regulating the function of "reproductive" neurons is new'.

The researchers, who are based at various institutions in Spain, France and Switzerland, used different mouse models to investigate the effects of suppressing Rank at various points during development. Embryonic loss of Rank led to severe HH in the animals, and its depletion in sexually mature mice also induced hypogonadism. Such results suggest that Rank signalling regulates the HPG axis in puberty and adulthood as well as during embryogenesis. Female mice exhibited more profound HH than males after Rank loss, which the researchers speculate may be due to sex-specific differences in microglia or the regulation of GnRH neurons. Further experiments demonstrated that the loss of Rank in hypothalamic microglia ultimately disrupted GnRH neuronal functionality, leading to HH in the mice.

Next, the team performed whole-exome sequencing in peripheral blood samples from 564 people with congenital HH. These individuals carried mutations in the RANK gene, supporting a similar role for the protein in human reproductive maturation and fertility.

'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 HH,' according to the authors.

Going forward, the authors suggest that RANK could be used as a candidate gene for the diagnosis of congenital HH in humans, as well as a therapeutic target in the treatment of fertility syndromes.