Title

Meiotic prophase arrest and resumption in mouse oocytes: A tale of two pathways

Date of Completion

January 2009

Keywords

Biology, Cell

Degree

Ph.D.

Abstract

In mammalian oocytes, the meiotic cell cycle is tightly controlled to make the best use of a limited number of germ cells. Oocytes arrest for prolonged periods in prophase I, until they are signaled to continue meiosis by luteinizing hormone (LH) from the pituitary. The signal from LH is indirect; it acts on outer cells of the ovarian follicle, and approximately 2-4 hours later, in mice, meiotic resumption occurs in the oocyte. In this thesis, I will present data that furthers our understanding of how meiotic arrest is maintained, and how the LH signal leads to re-initiation of the cell cycle in the oocyte. ^ In the oocyte, a G-protein coupled receptor (GPR3) is linked to G s and adenylyl cyclase to generate cAMP. In the studies to be described, we determine that this pathway is not controlled by contact with surrounding follicle cells, and that it is not terminated in response to LH stimulation. Instead, the LH signal reverses an inhibitory signal from the follicle cells, which maintains arrest prior to LH exposure. Specifically we find that cGMP enters the oocyte through gap junctions, inhibiting the activity of the oocyte cAMP phosphodiesterase, PDE3A. This in turn keeps the oocyte level of cAMP high, and prevents meiotic resumption. ^ Upon LH binding to outer follicle cells, two parallel pathways lead to a decrease in the concentration of oocyte cGMP. Firstly, LH causes a rapid decrease in the cGMP concentration in the follicle cells. Secondly, LH causes gap junctions between the follicle cells to close, disrupting the flux of cGMP into the oocyte. The resulting decrease in oocyte cGMP releases the inhibition of PDE3A, in turn leading to a decrease in oocyte cAMP. The fall in oocyte cAMP is in the regulatory range for PKA, allowing for the resumption of meiosis. ^