Microglia, known for scavenging debris and attacking pathogens, may also help regulate the hypothalamic-pituitary-gonadal axis, a new study shows. The findings, published in March in Science, suggest that microglia interact with and influence the function of hypothalamic neurons that release gonadotropin-releasing hormone (GnRH), which stimulates the pituitary to produce the hormones that spark ovulation and spermatogenesis.
“One of the biggest surprises was the role of microglia in controlling the GnRH neurons, because this is a link that hadn’t been seen before,” says study investigator Alejandro Collado-Solé, a postdoctoral researcher in Eva González-Suárez’s group at the Spanish National Cancer Research Center.
Microglia express a protein called RANK that is crucial to their effects on the hypothalamic-pituitary-gonadal axis. Knocking out RANK in mice reduces microglia’s interactions with GnRH neurons, lowers sex hormone levels and renders some of the animals infertile, the new study found.
“The fact that these specific interactions in such a small region of the brain can have such profound effects on fertility—a very fundamental aspect of the survival of a species—was quite unexpected,” says Annie Ciernia, assistant professor of biochemistry and molecular biology at the University of British Columbia, who was not involved in the research.
Microglia have been widely studied for their role in brain development, but the new study is the first to explore how these cells support the reproductive system.
“It’s surprising to me that nobody had looked at microglia in this system before,” because neuroendocrinology research “almost predates modern neuroscience,” says Margaret McCarthy, director of the Medicine Institute of Neuroscience Discovery at the University of Maryland, who was not involved in the work. “This should just highlight to all basic scientists that there’s still so much more going on with these immune cells than we think about,” she says.
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ANK is known to drive mammary gland development during pregnancy. But the RANK pathway’s function earlier in life was unclear.Mice that carry deletions in both copies of the RANK gene have defective testes and ovaries, though the changes are more pronounced in females than in males, González-Suárez and her colleagues found. The male mice produce less testosterone and have smaller testes than their wildtype littermates, whereas female mice are estradiol-deficient and have smaller uteri. In many of the female mice, the ovaries fail to produce a corpus luteum, which is critical for pregnancy. Both males and females also have unusually low levels of gonadotropins.
The team also engineered mice in which they could use the cancer drug tamoxifen to knock out RANK at the start of puberty, when the animals were 4 weeks old. Because tamoxifen affects the hypothalamic-pituitary-gonadal axis in females, the researchers tested only male mice, about half of which were infertile as adults. Many showed reduced testicular weight.
A genetic analysis of 564 people who have congenital hypogonadotropic hypogonadism, a condition characterized by low levels of gonadotropins and sex hormones, and often infertility, revealed that 6 of them (1 percent of the cohort) have a pathogenic variant in the RANK gene.
“Congenital hypogonadotropic hypogonadism is a human disease that displays the same symptoms or phenotype as the mouse model. And we found RANK mutations in these patients, showing RANK is related to human disease,” Collado-Solé says.
RANK is mainly expressed in microglia, according to the team’s analyses of transcriptomic data from mice and humans. Treating pubertal mice of both sexes with a drug called PLX3397 to deplete microglia led to decreases in testicular weight in males and the number of corpora lutea in females. The team found similar changes occurred in mice engineered to lack RANK in only their microglia. These mice also showed reduced GnRH expression.
What’s more, RANK deletion from all cells starting at puberty in male mice led to structural changes in microglia: The cells were smaller than usual, had fewer processes and made fewer contacts with GnRH neurons. These neurons also reacted less to kisspeptin, the protein that stimulates the production of GnRH.
Future research should tease apart “the control mechanism for initiating RANK activity in microglia,” Ciernia says.
