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

TLDR

Ovulation is a precisely timed, LH‑surge–initiated process that involves transcriptional regulation of genes and activation of proteases, with the progesterone receptor induced in granulosa cells and essential for ovulation. The authors used PR‑knockout mice to identify PR‑regulated genes in ovulation, demonstrating that MMP‑2 and MMP‑9 are not PR targets. They found that PR drives transcription of ADAMTS‑1 and cathepsin L, whose LH‑induced, PR‑dependent expression in granulosa cells suggests these proteases are critical for follicular rupture and advance understanding of ovulation proteolysis.

Abstract

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 progesterone receptor (PR), a nuclear receptor transcription factor, is induced 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 matrix metalloproteinases MMP-2 and MMP-9 are not targets of PR during ovulation. In contrast, two other proteases, ADAMTS-1 (A disintegrin and metalloproteinase with thrombospondin-like motifs) and cathepsin L (a lysosomal cysteine protease), are transcriptional targets of PR action. ADAMTS-1 is induced after LH stimulation in granulosa cells of preovulatory follicles and depends on PR. Cathepsin L is induced in granulosa cells of growing follicles by follicle-stimulating hormone, but the highest levels of cathepsin L mRNA occur in preovulatory follicles in response to LH in a PR-dependent manner. The identification of two regulated proteases in the ovary, together with their abnormal expression in anovulatory PR knockout mice, suggests that each plays a critical role in follicular rupture and represents a major advance in our understanding of the proteolytic events that control ovulation.