Researchers at the Francis Crick Institute have shown that gonadotrophs, cells in the pituitary gland with a key role in puberty and reproduction, come from two different populations, with the majority produced after birth rather than in the embryo, as previously thought.
A better understanding of when these important cells develop could help researchers and clinicians understand and treat disorders that impact puberty and fertility.
In the pituitary, a small gland located in the middle of the head and connected to the brain, gonadotrophs release hormones that stimulate the ovaries or testes to mature and start making eggs or sperm. Gonadotrophs first appear in the embryo and expand in number after birth.
A research team at the Crick previously identified a population of tissue-specific stem cells in the pituitary gland, which are cells that can self-renew or specialise into any cell type making up the tissue they are in.
These had no obvious function, although they could become any hormonal cell type in special contexts. Now, in research published today in Nature Communications, the same lab identified that these stem cells give rise to the bulk of the gonadotroph population after birth.
The team worked this out by genetically marking and tracing the descendants of the stem cells as they developed into different types in the pituitary gland in mice.
By following the markers from birth up to one year, the team saw that the stem cell pool almost exclusively became gonadotrophs rather than other types of pituitary cells. This process started after birth and continued until puberty in what is known as the 'minipuberty' period in mice.
They also showed that the two populations are located in separate compartments in the pituitary gland and that the embryonic gonadotrophs stay put throughout life, while the stem cell-derived population spread across the gland after birth.
The right recipe to produce gonadotrophs
Next, the team aimed to understand what stimulated the stem cells to become gonadotrophs specifically. They confirmed it needed to be something present in the body, because once isolated in the lab, the stem cells could become any pituitary cell type and not, as seen in the young animal, almost exclusively gonadotrophs.
The researchers first blocked a hormone made in the brain called gonadotrophin-releasing hormone (GnRH), which stimulates gonadotrophs to release hormones. This caused smaller ovaries and testes but still didn't stop the stem cells from becoming gonadotrophs, suggesting that GnRH isn't the signal stimulating their development. Similarly, removing sex hormones like testosterone, by giving the mice chemical blockers or removing the ovaries and testes, had no impact.
As GnRH and sex hormones didn't play a role in generating gonadotrophs, the team speculate that something about the physiological context, such as leaving the mother's body at birth, is important for gonadotrophs to develop at the right time.
Minipuberty: a window of opportunity
People with a rare genetic disorder called congenital hypogonadotropic hypogonadism (CHH) don't produce GnRH. This means gonadotrophs aren't stimulated to produce hormones that kickstart puberty, leading to absent or incomplete sexual development.
Similar to mice, humans also go through minipuberty, where a surge of activity in the pituitary gland takes place just after birth and lasts from a few months to years. The researchers also believe the same two subpopulations of gonadotrophs may exist in humans, suggesting that gonadotrophs are also mainly produced during minipuberty.
This highlights that there is a window of opportunity in early life to diagnose disorders like CHH or to check and intervene if gonadotrophs are forming properly. Identifying this earlier could prevent children from failing to go through puberty later in life.
Karine Rizzoti, Principal Laboratory Research Scientist in the Stem Cell Biology and Developmental Genetics Laboratory at the Crick and co-senior author, said: "We've known about this population of stem cells in the pituitary for a while, but it took the right tools used at the right time to see just how important they are. Instead of the previously held idea that gonadotrophs all have the same origin, we instead found that there are two waves of generation, before and after birth."
Daniel Sheridan, former PhD student at the Crick and first author, said: "Our discovery that gonadotrophs are mainly produced after birth is important as it highlights an opportunity to intervene, which would be difficult if they were mainly produced in the embryo. We haven't yet found what stimulates the stem cells to become gonadotrophs, which would help us understand how to treat conditions affecting puberty."
Robin Lovell-Badge, Principal Group Leader of the Stem Cell Biology and Developmental Genetics Laboratory at the Crick and co-senior author, said: "Now that we know there are two discrete populations of gonadotrophs, we can start to unpick which group is affected during disorders like CHH that cause delayed or absent puberty. The next step is to look at the role of each population in mice with similar disorders in puberty."
The researchers worked with many teams at the Crick, including the Biological Research Facility, the Genetic Modification Service and theBioinformatics and Biostatistics,Advanced Light Microscopy, Genomics, Flow Cytometry, and Histopathology teams.
