Regulation of Granulosa Cell Proliferation in the Rat

Abstract

The growth and maturation of the ovarian follicle is central to reproductive cyclicity in females. A_ fundamental aspect of follicle development is proliferation and differentiation of granulosa cells although the precise temporal dynamics and regulatory mechanisms remain largely unknown. Using the PMSG-primed immature rat as a model to study follicle growth, we show a decline in mural granulosa cell proliferation of large antral follicles prior to an ovulatory stimulus, although cumulus granulosa cells continue proliferating up to 10 h after an ovulatory bolus of hCG. Expression and activity of CCNE1-CDK2 correlates with granulosa cell cycle progression suggesting that regulators of this complex are likely to be key mediators of granulosa cell proliferation. Because of the spatial and· temporal organization of granulosa cell proliferation and differentiation within the follicle, we examined the relationship betw~en these two processes using both an in vivo and in vitro approach. By forcing proliferation in both of these models, we were unable to prevent an increase in markers of differentiation or in hCG/ forskolininduced markers of luteinization suggesting the uncoupling of granulosa cell proliferation and differentiation and/ or luteinization. The findings from these studies could have major implications hi contraceptive development, infertility treatment, and understanding and treatment of granulosa cell tumors.