DEVELOPMENTAL BIOLOGY When a woman is born, her ovaries already contain a full supply of the immature eggs she will need in her reproductive lifetime. Normally, these eggs begin ripening at about age 13 and are gradually released, usually at the rate of one per month, until she is about 50 years old. But in a small minority of women, perhaps 1 in 100, the ovaries stop releasing eggs much earlier in life, thus causing infertility and premature aging. Exactly why that happens isn't understood, but new results may help provide an explanation. On page [611][1], a team led by Kui Liu of Umea University in Sweden, reports that a gene called Pten , which is best known as a suppressor of tumor growth, is needed to keep egg development in check. In its absence, the researchers found, the egg-containing follicles of mice were activated rapidly at an early age, thus causing depletion of the animals' eggs much sooner than is normal—a situation similar to that of premature ovarian failure (POF) in humans. “It is a very nice piece of work that shows the importance of the PTEN pathway” in controlling follicle maturation in mice, says reproductive geneticist Aleksandar Rajkovic of Baylor College of Medicine in Houston, Texas. If PTEN also controls human egg maturation, the finding may aid the design of improved infertility treatments. Liu and his colleagues came to their conclusion by genetically engineering a mouse strain in which Pten expression was inactivated specifically in the animals' oocytes. The results showed that a functional Pten in oocytes is needed to keep egg follicles from maturing. Without it, Liu says, “all the primordial follicles were activated prematurely.” Once a follicle is activated, there's no going back. Its egg either matures and is released for fertilization or dies. As a result, the animals had one litter but were infertile by about 3 months of age, which is early adulthood for mice. By that same age, their ovaries had lost essentially all their follicles. The result is consistent with previous findings from Diego Castrillon, Ronald DePinho, and their colleagues at Harvard Medical School in Boston. About 5 years ago, they showed that knocking out the gene for the Foxo3a protein produced essentially identical effects ( Science , 11 July 2003, p. [215][2]). As it happens, Pten negatively regulates two other enzymes, PI3 kinase and Akt, which suppress Foxo3a. So with Pten gone, Foxo3a can't function. Castrillon's team, now at the University of Texas Southwestern Medical Center in Dallas, reported in the January issue of Human Reproduction that Foxo3a mutations are not a common cause of POF in humans. Still to be determined is whether mutations in PTEN or in other proteins that cooperate with PTEN in producing its cellular effects are involved with human ovarian problems. Even with that uncertainty, researchers think that the PTEN pathway is a good target for potential fertility treatments. Foxo3a and a number of other proteins shown to affect egg development in animals are transcription factors that regulate gene expression. But PTEN is an enzyme, and developing compounds that inhibit it, thus promoting egg development and maturation, should be easier. An enzyme “has the advantage of being easily manipulated,” says Aaron Hsueh, an ovarian physiologist at Stanford University School of Medicine in Palo Alto, California. ![Figure][3] Running out. Mouse ovarian tissue in which Pten was inactivated in oocytes ( left ) shows many activated follicles just 8 days after birth. But by 12 weeks ( right ), the mouse ovaries are depleted of follicles. CREDIT: P. REDDY ET AL. , SCIENCE He notes that although most women with POF are diagnosed after all their eggs are depleted, some still have follicles in their ovaries. It's impossible to tell when they will mature and release an egg, but treatment with a PTEN inhibitor could allow physicians to control that and perhaps help a woman become pregnant. Another possibility is to use a PTEN pathway inhibitor to aid follicle maturation in ovarian tissue in lab dishes, as may be needed for women who have had their ovaries removed prior to chemotherapy that would render them sterile. [1]: /lookup/doi/10.1126/science.1152257 [2]: /lookup/doi/10.1126/science.1086336 [3]: pending:yes
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