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Researchers at the Francis Crick Institute have made significant advancements in understanding the proteins that control the development of ovaries in mice, both before and after birth. This research is crucial in gaining insight into how female infertility develops. By identifying the gene responsible for initiating the development of ovaries in mouse embryos, the scientists aimed to determine which genes maintain ovarian functions, such as egg production, after birth.

Experimentation revealed that removing the Foxl2 gene in female mice at different stages of development resulted in varying effects. Removal during the embryonic stage led to abnormal ovaries and infertility in adult mice, while removal in adult mice caused their ovaries to resemble testes. In a study published in Science Advances, the team discovered that while FOXL2 plays a role in embryonic development, its impact is more significant after birth. The protein regulates the activity of numerous genes, including those essential for ovary functions like egg development.

FOXL2 is a protein that binds to specific regions in DNA, known as enhancers, and influences the expression of other genes. Through chromatin proteomics, researchers identified proteins that interact with FOXL2 while it is bound to DNA. They found a drastic increase in protein interactions in ovaries after birth compared to embryonic development. One such protein, USP7, binds to FOXL2 and plays a crucial role in ovary development, although its interaction with FOXL2 was previously unknown.

When the Usp7 gene was removed from female mice, they were unable to develop ovaries beyond puberty, leading to infertility. The researchers speculate that USP7 may be necessary to stabilize FOXL2 on DNA. In humans, both FOXL2 mutations and USP7 mutations can result in infertility, indicating their important roles in sexual development. Genetic testing is essential for diagnosing sexual development issues, and researchers are considering how gene editing techniques could be used for future treatments to address infertility.

The team, led by Robin Lovell-Badge and Roberta Migale, have made significant progress in understanding the genetic factors involved in female development and fertility. By uncovering the roles of FOXL2 and USP7, they have taken a step closer to understanding ovary development and function. Female development pathways are complex and have not been studied as extensively as male development, making this research particularly significant in addressing the global issue of infertility. The study was a collaborative effort involving various specialist teams at the Crick Institute, highlighting the interdisciplinary approach to research in this field.

Moving forward, the researchers plan to further investigate the role of the USP7 protein in sexual development. By utilizing their innovative approaches to studying protein interactions in ovaries, they hope to identify additional proteins that are essential for ovary development. Ultimately, shedding light on the key genes and proteins responsible for each stage of ovary development will be crucial in advancing our understanding of infertility and potentially developing new treatment strategies.

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