Feb. 2, 1999 A research team based at the Massachusetts General Hospital (MGH) has found that inactivation of a single gene in female mice can sustain ovarian function into advanced age. The report in the February issue of Nature Genetics describes how female mice in which a gene called Bax is inactivated do not experience the normal loss of ovarian cells that occurs throughout the animal' lifetime.
While these aged mice maintain a functioning supply of both oocytes (egg cells) and hormone-secreting granulosa cells, they do not ovulate or become pregnant under normal conditions. The research, which still is far from application in humans, may eventually lead to new techniques for delaying menopause and reducing its associated health risks.
"The Bax-deficient mice retained hundreds of ovarian follicles [tiny sacs containing an oocyte surrounded by granulosa cells] at an age when the ovaries are usually barren," says Jonathan Tilly, PhD, director of the MGH Vincent Center for Reproductive Biology and the paper's senior author. "And we were very pleased to find that the aged Bax-deficient mice appear to develop relatively normally in every other way."
Bax is one of a group of genes known to be key to programmed cell death -- the natural process by which unneeded cells are eliminated from the body. Previous research by the MGH-based team had shown that Bax expression was correlated with ovarian cell death in mice and humans. (Mammalian females are born with a set number of oocytes, more than 90 percent of which die off throughout the animal's lifetime.) Bax was first cloned by Stanley Korsmeyer, MD, a member of the research team who also produced the Bax-knockout mice. Korsmeyer was with the Howard Hughes Medical Institute at Washington University School of Medicine in St. Louis while this study was conducted and is now at the Dana-Farber Cancer Institute in Boston.
Pursuing the suggestion that inactivation of Bax could preserve ovarian cells, the research team compared Bax-deficient female mice with normal mice of the same ages. They found that, although both groups of mice have identical numbers of ovarian cells at birth, by puberty or shortly thereafter Bax-deficient females have three times as many immature egg-containing follicles as do the normal mice. Among mice reaching the very advanced age of 20 to 22 months, normal mice have exhausted their supply of both oocytes and granulosa cells, while the Bax-deficient mice maintain hundreds of follicles with functioning cells of both types.
Despite their healthy supply of ovarian cells, however, the aged Bax-deficient female mice do not ovulate and do not become pregnant when housed with young male mice. The researchers believe that a decline in regulatory hormone signals from the brain, among other normal, age-related bodily changes, causes the Bax-deficient females to become incapable of reproduction as they age.
"Prolonging general ovarian function -- separate from maintaining fertility -- holds great potential for benefiting women's health," Tilly says. "The cutoff in estrogen production that occurs with menopause increases women's risks of osteoporosis and heart disease and may be associated with other conditions like dementia. Although many women choose estrogen replacement therapy to reduce these risks, finding ways to prolong the body's natural estrogen production offers an exciting alternative."
Tilly stresses that no technology currently exists to apply this research in humans. Although the Bax-deficient mice showed no adverse health effects from the gene knockout, including no cancers, human application would require selectively blocking the gene's expression in the ovary alone, something that currently is impossible.
The study was led by Gloria Perez, DVM, PhD, and Rodolfo Robles, MD, both of the MGH Vincent Center for Reproductive Biology. In addition to Tilly and Korsmeyer, the study's other co-authors are Michael Knudson, MD, PhD, of the Howard Hughes Medical Institute at Washington University School of Medicine in St. Louis, and Jodi Flaws, PhD, of the MGH and the University of Maryland School of Medicine. The study was supported by grants from the National Institutes of Health and Vincent Memorial Research Funds.
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