News | New study finds immune cells and RANK protein help regulate fertility
A new study found that immune cells in the brain and a protein called RANK may play key roles in regulating the onset of puberty and reproductive capacity. Researchers say the discovery offers a new perspective on reproductive regulation and may identify new targets for diagnosing and treating certain endocrine disorders and infertility.
The study was conducted by a team at the Spanish National Cancer Research Centre (Centro Nacional de Investigaciones Oncológicas, CNIO) and published in Science.
The onset of puberty depends on the hypothalamic-pituitary-gonadal axis
Human puberty begins in the brain. Specifically, certain neurons in the hypothalamus release gonadotropin-releasing hormone (GnRH), which then activates the pituitary gland at the base of the skull. The pituitary releases other hormones that initiate maturation of the gonads—the ovaries or testes.
This regulatory system is known as the hypothalamic-pituitary-gonadal (HPG) axis and is an important endocrine mechanism governing reproductive function.
Previous research established that other neurons regulate GnRH neurons, but the new study identifies a previously unrecognized participant in this system: immune cells in the central nervous system.
Microglia found to help regulate the reproductive axis
The team found that microglia in the brain can regulate the function of GnRH neurons.
Microglia are important immune cells in the central nervous system. Their main function is to remove potential threats and molecules that are no longer needed, helping maintain nervous system stability.
Study lead Eva González-Suárez, head of CNIO's Cancer Cell Biology Programme, said it was significant that the cells involved in regulating fertility were immune cells rather than neurons.
The study further showed that microglia regulate GnRH neuron activity by expressing the RANK protein.
RANK was previously known mainly for its role in bone remodeling and also has an important function in the mammary gland. In 2010, González-Suárez's team found that RANK plays a key role in breast cancer development.
Loss of RANK causes reproductive abnormalities
In animal models, researchers suppressed RANK expression to observe its effects on the reproductive system.
Reproductive function was markedly impaired in both male and female animals when RANK signaling was suppressed.
Animals born without RANK, or in which it was removed before puberty, had markedly lower sex hormone levels, developed hypogonadism, and did not enter puberty normally.
When RANK was deleted in sexually mature animals, they lost fertility within one month.
These findings indicate that RANK signaling plays an important role in maintaining normal reproductive function.
Study identifies related gene mutations in humans
To assess whether this mechanism is relevant to human fertility, the team genetically analyzed samples from patients with congenital hypogonadotropic hypogonadism.
This rare disorder typically causes delayed or absent puberty and infertility. Previous research attributed it mainly to abnormal GnRH neuron function or defects in related molecules.
The new study found mutations in the gene encoding RANK in some patients.
Researchers said this suggests that RANK may not only be a potential treatment target for endocrine disorders and infertility but also a candidate biomarker for diagnosing congenital hypogonadotropic hypogonadism.
Potential effects on multiple neuroendocrine systems
González-Suárez said the finding that microglia regulate “reproductive neurons” through RANK signaling is entirely new.
She added that this mechanism may not be limited to the reproductive axis and could affect other neuroendocrine systems, including those controlling appetite and satiety and the stress-response axis.
If further confirmed, the mechanism could broaden understanding of interactions between the immune and neuroendocrine systems.
Interdisciplinary collaboration drives the breakthrough
The team also emphasized that the findings resulted from interdisciplinary collaboration.
First author and CNIO researcher Alejandro Collado said the study began with a question from his doctoral thesis: whether RANK plays a role in mammary gland development during puberty.
As the work progressed, the team realized that it involved the reproductive system, neuroscience, and brain cells, prompting collaboration with researchers from different disciplines.
Participating institutions included the University of Córdoba and Maimónides Biomedical Research Institute (IMIBIC) in Spain, the French National Institute of Health and Medical Research (Inserm), the Institute of Biomedicine of Seville (IBiS) in Spain, and Lausanne University Hospital (CHUV) in Switzerland.
Collado said interdisciplinary collaboration led the team to conclusions they could not initially have anticipated and gave them new research techniques and tools that will support future work.
News | New study finds immune cells and RANK protein help regulate fertility
News | New study finds immune cells and RANK protein help regulate fertility
A new study found that immune cells in the brain and a protein called RANK may play key roles in regulating the onset of puberty and reproductive capacity. Researchers say the discovery offers a new perspective on reproductive regulation and may identify new targets for diagnosing and treating certain endocrine disorders and infertility.
The study was conducted by a team at the Spanish National Cancer Research Centre (Centro Nacional de Investigaciones Oncológicas, CNIO) and published in Science.
The onset of puberty depends on the hypothalamic-pituitary-gonadal axis
Human puberty begins in the brain. Specifically, certain neurons in the hypothalamus release gonadotropin-releasing hormone (GnRH), which then activates the pituitary gland at the base of the skull. The pituitary releases other hormones that initiate maturation of the gonads—the ovaries or testes.
This regulatory system is known as the hypothalamic-pituitary-gonadal (HPG) axis and is an important endocrine mechanism governing reproductive function.
Previous research established that other neurons regulate GnRH neurons, but the new study identifies a previously unrecognized participant in this system: immune cells in the central nervous system.
Microglia found to help regulate the reproductive axis
The team found that microglia in the brain can regulate the function of GnRH neurons.
Microglia are important immune cells in the central nervous system. Their main function is to remove potential threats and molecules that are no longer needed, helping maintain nervous system stability.
Study lead Eva González-Suárez, head of CNIO's Cancer Cell Biology Programme, said it was significant that the cells involved in regulating fertility were immune cells rather than neurons.
The study further showed that microglia regulate GnRH neuron activity by expressing the RANK protein.
RANK was previously known mainly for its role in bone remodeling and also has an important function in the mammary gland. In 2010, González-Suárez's team found that RANK plays a key role in breast cancer development.
Loss of RANK causes reproductive abnormalities
In animal models, researchers suppressed RANK expression to observe its effects on the reproductive system.
Reproductive function was markedly impaired in both male and female animals when RANK signaling was suppressed.
Animals born without RANK, or in which it was removed before puberty, had markedly lower sex hormone levels, developed hypogonadism, and did not enter puberty normally.
When RANK was deleted in sexually mature animals, they lost fertility within one month.
These findings indicate that RANK signaling plays an important role in maintaining normal reproductive function.
Study identifies related gene mutations in humans
To assess whether this mechanism is relevant to human fertility, the team genetically analyzed samples from patients with congenital hypogonadotropic hypogonadism.
This rare disorder typically causes delayed or absent puberty and infertility. Previous research attributed it mainly to abnormal GnRH neuron function or defects in related molecules.
The new study found mutations in the gene encoding RANK in some patients.
Researchers said this suggests that RANK may not only be a potential treatment target for endocrine disorders and infertility but also a candidate biomarker for diagnosing congenital hypogonadotropic hypogonadism.
Potential effects on multiple neuroendocrine systems
González-Suárez said the finding that microglia regulate “reproductive neurons” through RANK signaling is entirely new.
She added that this mechanism may not be limited to the reproductive axis and could affect other neuroendocrine systems, including those controlling appetite and satiety and the stress-response axis.
If further confirmed, the mechanism could broaden understanding of interactions between the immune and neuroendocrine systems.
Interdisciplinary collaboration drives the breakthrough
The team also emphasized that the findings resulted from interdisciplinary collaboration.
First author and CNIO researcher Alejandro Collado said the study began with a question from his doctoral thesis: whether RANK plays a role in mammary gland development during puberty.
As the work progressed, the team realized that it involved the reproductive system, neuroscience, and brain cells, prompting collaboration with researchers from different disciplines.
Participating institutions included the University of Córdoba and Maimónides Biomedical Research Institute (IMIBIC) in Spain, the French National Institute of Health and Medical Research (Inserm), the Institute of Biomedicine of Seville (IBiS) in Spain, and Lausanne University Hospital (CHUV) in Switzerland.
Collado said interdisciplinary collaboration led the team to conclusions they could not initially have anticipated and gave them new research techniques and tools that will support future work.
Story source:
Collected online