The study aims to understand how female fertility is constructed at the molecular level

The study aims to understand how female fertility is constructed at the molecular level

Fertility is finite for female mammals. From birth, women possess a limited number of primordial follicles, collectively known as the ovarian reserve. Inside each follicle is an oocyte, which eventually becomes an egg. But as we age, the follicles in the ovarian reserve decrease.

Despite its fundamental importance, our understanding of how ovarian reserve is established and maintained remains poor.”

Satoshi Namekawa, Professor, Department of Microbiology and Molecular Genetics, University of California, Davis

Researchers define the epigenetic machinery that regulates the structure and function of the mammalian ovarian reserve and provide molecular insights into women's reproductive health and lifespan in a new study published August 10 in Nature Communications. Epigenetics refers to changes that affect how genes function without changing the DNA itself. Lead scientists on the paper include Namekawa, project scientist Mengwen Hu, and UC Davis professors Richard Schultz and Neil Hunter.

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

Stopping original production

When the ovarian reserve is built up, all eggs in the primordial follicles stop their development and can remain in such a arrested state for decades.

“Fertility is supported by these arrested oocytes,” Namekawa said, noting that a previously unknown molecular machinery halts development. "The main question is, how can these cells be maintained for decades? That's a big question. They can't divide, they can't reproduce, they just sit quietly in the ovaries for decades. How is that possible?"

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

A molecular understanding of fertility

PRC1 suppresses the developmental process called meiosis, which occurs before the establishment of the ovarian reserve, thereby ensuring a proper gene expression program in the ovarian reserve. When the team created mouse mutants with depleted PRC1 machinery, they found that ovarian reserve could not be built up and the cells suffered cell death.

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

According to Namekawa and his colleagues, defects in PRC1 function could help explain cases of premature ovarian failure and infertility in humans.

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

Other authors of 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. The work was supported by grants from the NIH.

Source:

University of California – Davis

Reference:

Hu, M. et al. (2022) PRC1-mediated epigenetic programming is required to generate ovarian reserve. Nature communication. doi.org/10.1038/s41467-022-31759-6.

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