For the first time, scientists have identified how the ovarian reserve, which underpins mammalian female fertility, is established. Published in the journal Nature Communications, a new study provides much-needed insight into the molecular basis of female reproductive health, in mice at least.
The “ovarian reserve” is essentially an indicator of the ovary's capacity to provide eggs that could be fertilized and result in a viable pregnancy. Specifically, it refers to the number of primordial follicles – follicles found in mammalian ovaries which each contain an oocyte that later develops into an egg – that a person has. The number of primordial follicles is finite in mammals – we are born with a certain amount and don’t develop more – and, unfortunately, as we age the number of follicles we have dwindles.
This plays a massively important role in female fertility, and yet relatively little is known about it.
“Despite its fundamental importance, our understanding how the ovarian reserve is established and maintained remains poor,” co-author Professor Satoshi Namekawa of the Department of Microbiology and Molecular Genetics at the University of California, Davis said in a statement.
But with this new study, that has now changed. The researchers have been able to define, in mice, specific epigenetic changes – reversible changes that affect gene expression but don’t affect DNA sequence – which explain the establishment of the reserve that has perplexed scientists for so long.
And the real-world implications of this could be huge, the authors say: “Our study may give us the foundation to understand how female fertility is established and maintained at the molecular level and why it declines with age,” Namekawa added.
Prior to the establishment of the mammalian ovarian reserve, oocytes can pause a key developmental process called meiosis. Meiosis occurs when egg or sperm cells divide and reduce their genetic material so that each cell only has one copy of each chromosome. Avoiding this, oocytes can stay in an arrested state for decades, which we already know is what establishes the ovarian reserve and therefore defines the female reproductive lifespan. However, what we didn’t know until now is exactly how oocytes are able to stay in this state for so long.
In a series of mouse studies, the team identified a key group of proteins that oversee the developmental pause. Polycomb Repressive Complex 1 (PRC1) mediates gene silencing and, the authors revealed, is essential in establishing the arrested state. When PRC1 was mutated so that it no longer functioned, the ovarian reserve could not be established and mice experienced premature ovary failure.
“We show that a conditional PRC1 deletion results in rapid depletion of follicles and sterility,” said Namekawa. “These results strongly implicate PRC1 in the critical process of maintaining the epigenome of primordial follicles throughout the protracted arrest that can last up to 50 years in humans.”
We might finally know a little more about the establishment of the ovarian reserve, but as for its inner workings, there are still questions to be answered:
“Can we uncover a more detailed mechanism of this process? How can the ovarian reserve be maintained for decades?” Namekawa asked. Watch this space.