Under arrest

An oocyte with a polar body within an antral follicle of a Gpr3^−/− ovary. Image kindly provided by Laurinda Jaffe, University of Connecticut Health Center, Farmington, CT, USA.

Mammalian oocytes are arrested in prophase of meiosis from a time before birth. Then, during reproductive life, luteinizing hormone (LH) induces the resumption of meiosis, which results in a haploid set of chromosomes in preparation for fertilization. Researchers reporting in Science have now shed light on how meiotic arrest is maintained in mouse oocytes up until the time that LH induces the resumption of meiosis and ovulation.

The heterotrimeric G protein G_s had previously been shown to be required for meiotic arrest, so Mehlmann and Jaffe, in collaboration with Eppig and colleagues, searched a database of genes that are expressed in mouse oocytes, looking for a receptor that activates G_s. The search identified the orphan G_s-linked receptor GPR3, which increases cyclic-AMP concentrations. This was an interesting result because G_s is known to keep cAMP concentrations elevated, which is important for meiotic arrest. Next, they showed that Gpr3 mRNA was present in oocytes, and that the concentration of Gpr3 transcripts was ∼14 times higher than in the surrounding somatic cells of antral (or resting) follicles.

To probe the function of GPR3, Mehlmann, Jaffe and co-workers analysed the ovaries of Gpr3-knockout mice. The ovaries were normal in terms of their external morphology, growth and ovulatory activity. However, 82% of the oocytes within antral Gpr3^−/− follicles had resumed meiosis, and almost half of these were in metaphase II. Only 37% of oocytes from early antral Gpr3^−/− follicles resumed meiosis, whereas all oocytes in pre-antral Gpr3^−/− follicles remained arrested in prophase. So, depending on the developmental stage of the follicles, oocytes that lacked GPR3 resumed meiosis.

Next, the authors showed that the resumption of meiosis in Gpr3^−/− follicles was independent of LH. The action of LH would normally lead to the deposition of extracellular material around the somatic granulosa cells, which results in an expanded follicle — but this was not the case in these mutants. In fact, the only detected defect in Gpr3^−/− follicles was the failure to maintain meiotic arrest. This phenotype could be reversed by injecting Gpr3 RNA into oocytes from Gpr3^−/− pre-antral or very early antral follicles and letting the follicles grow in culture. Only 11% of the injected oocytes had resumed meiosis after a 4-day culture period, compared with about half of non-injected oocytes.

Together, these data indicate that GPR3 is a negative regulator of meiotic progression in mouse oocytes. Future studies will undoubtedly look into how LH might relieve the arrest and reinitiate meiosis as well as try to identify the ligands that interact with GPR3.