Eggs under arrest: Jackson Laboratory team finds out 'who dunnit'

In research published in the journal Science, Eppig, along with visiting investigator Dr. Meijia Zhang of the State Key Laboratory for Agrobiotechnology in Beijing, reported their discovery of an exquisitely orchestrated sequence of signals between the oocytes, the cells that become eggs, and other nearby cells within ovarian follicles.

Inside the ovaries, immature egg cells known as oocytes are waiting for their big moment. During each estrous cycle only a few oocytes develop into fully mature eggs (usually just one in a typical human menstrual cycle).

Mammals reproduce through the meeting of an egg and a sperm, each of which has exactly half the normal number of chromosomes. The fusion produces a cell with a complete set (46 in human cells) that holds the potential to produce an adult mammal.

Meiosis is the process through which reproductive cells cut their chromosome number in half. It’s a continual process in adult males, who constantly produce viable sperm. But for adult females, timing is critical. Their eggs, usually released one at a time in women, are held in what’s known as meiotic arrest from birth through ovulation. It’s only when they are ready to be released from the ovary that meiosis is completed and the egg is ready for fertilization. Any disruption of the timing can impede fertility.

Researchers have long known that follicular granulosa cells–the cells in the follicle that surround the oocyte–prevent premature meiosis in oocytes by delivering a signaling molecule, cGMP. This maintains the oocytes’ immature state until a surge of hormones triggers ovulation. But no one knew how the production of arresting cGMP was regulated in the granulosa cells.

Eppig and Zhang, working with mice, uncovered the final pieces of the meiotic-arrest puzzle. Zhang was focusing on certain functions of a small regulatory peptide, called NPPC, and its molecular receptor called NPR2 when Eppig saw that there were bigger fish to catch.

“I thought he was looking at an important regulatory processes in the ovarian follicles, but that by taking a broader view we might find a more exciting result,” says Eppig.

What they found was an intricate interrelationship of signaling between the oocytes themselves, the cumulus cells, which are specialized granulosa cells surrounding the oocytes, and the follicular granulosa cells. NPPC from the follicle cells bind to a receptor, NPR2, on the cumulus cells and stimulate the production of cGMP that is transferred to the oocyte to maintain meiotic arrest. The oocytes themselves also get into the act, promoting production of NPR2 in the cumulus cells that surround them. Mutant mice lacking either NPPC or NPR2 were not able to maintain meiotic arrest.

Eppig says further research in his lab will explore the mechanism behind resumption of meiosis when the signal comes (called the luteinizing hormone surge) that triggers ovulation. A better understanding of meiotic processes could provide the basis for future fertility treatments or contraceptives or avoid the problems that cause birth defects.

The Jackson Laboratory is a nonprofit biomedical research institution based in Bar Harbor, Maine. Its mission is to discover the genetic basis for preventing, treating and curing human diseases, and to enable research and education for the global biomedical community.

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Zhang et al.: Granulosa Cell Ligand NPPC and Its Receptor NPR2 Maintain Meiotic Arrest in Mouse Oocytes. Science, published online October 14, 2010, doi 10.1126/science.1193573.

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