Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases

Ovulation is a precisely timed process by which a mature oocyte is released from an ovarian follicle, This process is initiated by the pituitary surge of luteinizing hormone (LH). is temporally associated with transcriptional regulation of numerous genes, and is presumed to involve the synthesis and /or activation of specific proteases that degrade the follicle wall. The pr ogesterone receptor (PR), a nuclear receptor transcription factor, is induc ed in granulosa cells of preovulatory follicles in response to the LH surge and has been shown to be essential for ovulation, because mice lacking PR fail to ovulate and are infertile, Using these mice as a model in which to elucidate PR-regulated genes in the ovulation process, we show that the mat rix metalloproteinases MMP-2 and MMP-9 are not targets of PR during ovulati on, In contrast, two other proteases, ADAMTS-1 (A disintegrin and metallopr oteinase with thrombospondin-like motifs) and cathepsin L (a lysosomal cyst eine protease), are transcriptional targets of PR action. ADAMTS-1 is induc ed after LH stimulation in granulosa cells of preovulatory follicles and de pends on PR. Cathepsin L is induced in granulosa cells of growing follicles by follicle-stimulating hormone, but the highest levels of cathepsin L mRN A occur in preovulatory follicles in response to LH in a PR-dependent manne r. The identification of two regulated proteases in the ovary, together wit h their abnormal expression in anovulatory PR knockout mice, suggests that each plays a critical role in follicular rupture and represents a major adv ance in our understanding of the proteolytic events that control ovulation.