Full basket. Ovaries without Foxo3a (right) bulge with surplus follicles.

Mutation in Mice Triggers Ovarian Failure

A protein in female mice makes sure their eggs mature at the right pace, new research shows. The master protein may help researchers understand why some women hit menopause decades earlier than they should.

Female mammals are born with all the eggs they'll ever have. Every menstrual cycle, a clutch of premature eggs, called follicles, starts to develop in the ovaries. The vast majority die, with only one (in humans) or several (in rodents) making it all the way to the uterus, a process called ovulation. When a woman runs out of follicles, she reaches menopause, usually around the age of 50.

About 1% of women, though, reach menopause in their 30s, a condition called premature ovarian failure. Scientists don't understand what causes the disorder, but they've found a handful of genes that could be involved. Pathologist Diego Castrillon of Harvard Medical School in Boston and colleagues took a closer look at one of these fertility-related genes, Foxo3a, to determine what role it might play.

The team engineered mice that lacked both chromosomal copies of the Foxo3a gene. The mice were healthy but anemic. At first, the mutant animals birthed broods of about the same size as those of normal mice, but subsequent pregnancies resulted in ever fewer offspring. By about 15 weeks of age, the Foxo3a-deficient mice became sterile. (Normal mice continue to breed for well over a year.) But at about 4.5 weeks, the mutant mice had about 100 extra follicles growing in their ovaries. When the team induced ovulation in the animals, the mutants produced close to the same number of mature eggs as typical mice did, suggesting that Foxo3a wasn't needed for normal ovulation.

Taken together, the results indicate that Foxo3a keeps follicles in check. "Maybe women with premature ovarian failure have a higher rate of follicular activation," says Castrillon, whose team reports its results in the 10 July issue of Science.

Reproductive biologist Aaron Hsueh of Stanford University Medical School calls the study "very exciting." He says it helps researchers understand the molecular mechanism that activates follicle growth, but the human equivalent of Foxo3a has not yet been found.

Related sites
Diego Castrillon's page at Harvard Medical School
Co-author Ronald DePinho's page at Harvard Medical School