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Pathology
Sorting Good Eggs from Bad Ones
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Death of Oocytes Could Shed Light on Infertility, Miscarriage
Clusters of unfertilized eggs die and pass from a woman's body each month, but the loss pales in comparison to the culling of eggs that occurs in the ovaries at birth. More than half of the egg cells produced during fetal life die—about three million out of an original five—apparently by committing suicide.
Despite the magnitude of the destruction, biologists know very little about why or how the cells kill themselves in the days just before and after birth. Do they commit suicide because they are defective? Does their sacrifice benefit the survivors? In their search for answers, Keith Blackwell, Rosa Navarro, and their colleagues have uncovered a critical clue—one that could lead to a better understanding not just of why some eggs die but also what makes an oocyte fertile.
Many worm oocytes die at an early age. Nematodes exist in one of two reproductive states—as males, producing only sperm; and as hermaphrodites, producing both sperm and eggs, which can self-fertilize in their gonads (below). Normally, more than half of worm oocytes produced in a hermaphrodite's gonads commit suicide after the pachytene stage of meiosis (above left). Rosa Navarro, Keith Blackwell, and their colleagues found that the CGH-1–deprived hermaphrodites could not bear young because their oocytes had all committed cellular suicide (above right). Images adapted from originals by Navarro/Blackwell
Though egg cells are killed by the same proteins—caspases—that operate in other cell suicides, studies in worms have suggested that the caspases are triggered by a unique set of signals in eggs. Now, Navarro, Blackwell, and their colleagues have identified one such signal—a defect in a protein needed for processing RNA. In worms lacking this protein, CGH-1, oocytes underwent mass suicide.
"We've identified an abnormality of oogenesis that triggers apoptosis," said Blackwell, HMS associate professor of pathology. Even when the defective cells were rescued from death, they could not be fertilized, suggesting they were nonfunctional. The findings appear in the Sept. 1 Development.
On the face of it, the oocytes appear to be using their suicide machinery to sort the good eggs from the bad. Yet nearly half of worm egg cells commit suicide, and it is unlikely that they all are defective.
"When you think about what a human oocyte has to do, it is really astounding," said Keith Blackwell. "You have this cell that is ready to be kick-started and fertilized and ready to just run and go—in some cases, after decades." He appears with Rosa Navarro.
Blackwell, who is an investigator at the Center for Blood Research, believes that the egg cells could be using their apoptotic machinery to serve two cellular functions. On the one hand, it winnows out defective egg cells. But it may also be a way of getting perfectly healthy cells to sacrifice themselves for a greater good.
Such altruistic behavior is actually fairly common. In flies and hydra, large numbers of apparently healthy oocytes die and donate cytoplasm to their neighbors. Doing so, these "nurse cells" ensure the well-being of the survivors. Researchers have suggested that something similar may happen in worm oocytes which, early in embryonic life, live in one contiguous community.
"It's a reasonable hypothesis that this apoptotic mechanism evolved to give you cells that are nurse cells and that reproduction works more efficiently this way," Blackwell said.
Human egg cells have not been observed to donate cytoplasm to one another, though they are connected. And infertility and other reproductive problems appear to be due to the dying off of oocytes decades after birth. Still, the findings in worm oocytes could shed light on questions of human concern, such as infertility. "I think we're plugging into something that's involved with what makes a good oocyte," Blackwell said. Being able to distinguish good oocytes from bad could yield information about the potential for birth defects, miscarriages, and infertility.
—Misia Landau
Copyright 2001 by the President and Fellows of Harvard College
