December 4, 2022

The PRC1 gene complex is needed to establish ovarian reserve. Deletion of the PRC1 gene complex in mice resulted in the death of primordial follicles in the ovary. Wild-type mice at the top, PRC1 deleted mice below. Credit: Satoshi Namekawa, UC Davis

Fertility is finite for female mammals. From birth, females possess a limited number of primordial follicles, collectively referred to as the ovarian reserve. Within each follicle is an egg that eventually becomes an egg. But with age, the follicles in the ovarian reserve decrease.


“Despite its fundamental importance, our understanding of how the ovarian reserve is built and maintained remains poor,” said Professor Satoshi Namekawa, Department of Microbiology and Molecular Genetics at the University of California, Davis.

Researchers define the epigenetic machinery that regulates the establishment and function of the mammalian ovarian reserve, providing molecular insights into female reproductive health and longevity, in a new study published Aug. 10 in nature communication. Epigenetics refers to changes that affect how genes work without changing the DNA itself. Leading scientists on the paper include Namekawa, project scientist Mengwen Hu, and UC Davis professors Richard Schultz and Neil Hunter.

“In human women over the age of 35, you see a decline in fertility,” Namekawa said. “Our study can give us the foundation for understanding how female fertility is established and maintained at the molecular level and why it declines with age.”

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When the ovarian reserve is established, all the eggs in the primordial follicles pause their development and can remain in such a blocked state for decades.

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“Fertility is supported by these arrested eggs,” Namekawa said, pointing out that a previously unknown molecular machine is interrupting development. “The main question is how can these cells be maintained for decades? It’s a big question. They can’t divide, they can’t multiply, they just stay in the ovaries for decades at rest. How is this possible?”

Using mouse mutants, the team found that pausing this oocyte transition phase was mediated by a group of proteins called the Polycomb Repressive Complex 1 (PRC1).

A molecular understanding of fertility

PRC1 suppresses the developmental process called meiosis that occurs prior to the establishment of the ovarian reserve, thus ensuring a proper gene expression program in the ovarian reserve. When the team created mouse mutants with depleted PRC1 machines, they found that ovarian reserve could not be determined and the cells were undergoing cell death.

“We show that a conditional PRC1 deletion results in rapid follicles depletion and sterility,” Namekawa said. “These results strongly implicate PRC1 in the critical process of maintaining the epigenome of primordial follicles during the prolonged shutdown that can last up to 50 years in humans.”

According to Namekawa and his colleagues, deficiencies in PRC1 functionality may help explain cases of premature ovarian failure and infertility in humans.

“Now that we have discovered that this epigenetic process is key to settlement, the next question is whether we can discover a more detailed mechanism of this process?” said Namekawa. “How can the ovarian reserve be maintained for decades?”

Other authors on the paper include: at UC Davis, Yu-Han Yeh, Yasuhisa Manukata, and Hironori Abe; Akihiko Sakashita and So Maezawa, Cincinnati Children’s Hospital Medical Center; Miguel Vidal, Centro de Investigaciones Biológicas Margarita Salas, Madrid, Spain; and Haruhiko Koseki, RIKEN Center for Allergy and Immunology, Yokohama, Japan.

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More information:
PRC1-mediated epigenetic programming is required to generate the ovarian reserve, nature communication (2022). DOI: 10.1038/s41467-022-31759-6

Quote: Study Reveals How Ovarian Reserve Was Determined (2022, Aug. 10) Retrieved Aug. 10, 2022 from https://phys.org/news/2022-08-reveals-ovarian-reserve.html

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