Abstract
Mammalian oocytes are arrested in meiotic prophase by an inhibitory
signal from the surrounding somatic cells in the ovarian follicle.
In response to luteinizing hormone (LH), which binds to receptors
on the somatic cells, the oocyte proceeds to second metaphase, where
it can be fertilized. Here we investigate how the somatic cells regulate
the prophase-to-metaphase transition in the oocyte, and show that
the inhibitory signal from the somatic cells is cGMP. Using FRET-based
cyclic nucleotide sensors in follicle-enclosed mouse oocytes, we
find that cGMP passes through gap junctions into the oocyte, where
it inhibits the hydrolysis of cAMP by the phosphodiesterase PDE3A.
This inhibition maintains a high concentration of cAMP and thus blocks
meiotic progression. LH reverses the inhibitory signal by lowering
cGMP levels in the somatic cells (from approximately 2 microM to
approximately 80 nM at 1 hour after LH stimulation) and by closing
gap junctions between the somatic cells. The resulting decrease in
oocyte cGMP (from approximately 1 microM to approximately 40 nM)
relieves the inhibition of PDE3A, increasing its activity by approximately
5-fold. This causes a decrease in oocyte cAMP (from approximately
700 nM to approximately 140 nM), leading to the resumption of meiosis.
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