Sci. Aging Knowl. Environ., 15 June 2005
Before Their Time
Eggs falter prematurely in mice without signaling molecule
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/24/nf44
Like young wines, immature eggs, known as oocytes, must chill out for years. Now, research reveals that a molecule that helps unveil oocytes at the right moment also staves off age-related infertility. Understanding the mechanisms involved could reveal ways to maintain women's childbearing capacities later in life.
Career aspirations or grad school can cause women to put off motherhood. But female fertility drops off with age, so women who postpone pregnancy can encounter difficulty conceiving. Researchers want to understand the mechanisms that lead to infertility in the hopes of delaying it. Reproduction depends on having burgeoning eggs ready but not activating them until the right moment; if they wake up too soon, they die before they can be fertilized. Ovaries make oocytes by splitting cells with two copies of each chromosome into cells with only one copy each, a process called meiosis. Oocyte production starts before a female baby is born, but meiosis stalls partway through; oocytes only resume division years later when it's time for ovulation. A signaling molecule called cyclic AMP (cAMP) restrains oocytes from dividing until the proper time, and a protein called GPR3 helps make cAMP by activating the enzyme that produces it. While studying other aspects of GPR3, Ledent and colleagues discovered that mice lacking the protein have reproductive glitches. Although the animals grow and mature normally, females without GPR3 lose fertility unusually rapidly. They bear smaller litters at every age than do normal mice, and the number of pups per pregnancy declines more quickly as they get older compared to normal mice.
To explore how GPR3 influences reproductive decline during aging, the team collected oocytes from 3.5-week-old and 6-month-old mice. At both ages, about one-third of cells from genetically altered animals had restarted division, whereas few oocytes from normal mice had split. The findings confirm previous results, which showed that GPR3 restrains cell division. In old and young mice without GPR3, a similar percentage of oocytes had resumed splitting, indicating that age-related infertility didn't accelerate because more oocytes divide prematurely in older animals.
Next, the team mated GPR3-less females to normal males and assessed the health of their embryos. In altered females, fewer embryos reached later developmental stages compared with embryos from normal females. Moreover, the proportion decreased as animals aged. That finding suggests that GPR3's function in oocytes somehow helps promote the formation of vigorous embryos in older mothers. The researchers aren't sure how GPR3 bolsters embryos, but animals without it might be more likely to release defective oocytes, the researchers posit.
"This article helps us understand some of the molecular mechanisms that might underlie ovarian aging in humans," says reproductive endocrinologist Karen Berkowitz of the University of Pennsylvania in Philadelphia. Next, scientists should determine whether human oocytes also produce GPR3, and whether glitches in the protein underlie cases of human infertility, says cell biologist Lisa Mehlmann of the University of Connecticut Health Center in Farmington. That work could help reveal new ways to keep women in their prime longer.
June 15, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150