EGFR Signaling Is Necessary for Gonadotropin-Induced Steroidogenesis and Oocyte Maturation
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The mid-cycle luteinizing hormone (LH) surge triggers ovarian processes that are critical for normal female fertility, including steroidogenesis, oocyte maturation, and subsequent ovulation. Studies were designed to examine the LH-induced signaling pathways that regulate ovarian steroidogenesis, as well as the subsequent role of steroids and their receptors on oocyte and follicle development. Initial work focused on transcriptionindependent, or nongenomic, steroid-induced maturation of oocytes. We demonstrated for the first time that steroids trigger oocyte maturation in several different mouse models, activating G protein signaling, as well as MAPK and CDK1/cdc2 intracellular signaling cascades. Pharmacologic studies using receptor antagonists as well as transgenic mouse models suggested that steroid-induced maturation is mediated through classical steroid receptors. Subsequent studies focused on LH-induced signals that regulate steroidogenesis in the mouse ovary. We found that EGF triggered steroid production in three separate models of follicle culture and surprisingly, EGF receptor signaling was absolutely necessary for LHinduced steroidogenesis in an intact follicle. In addition, studies performed in testicular Leydig cells and adrenal cells revealed that EGF receptor signaling is required for normal steroid production, making this a universal signaling pathway in steroid physiology. In summary, our data suggest a model whereby stimulation of LH receptors in theca and mural granulosa cells activates matrix metalloproteinases (MMP) to cleave membrane-bound EGF moieties. The soluble EGF molecules then stimulate EGFRs on granulosa cells (and possibly theca cells), leading to activation of StAR and increased steroidogenesis. The steroids in turn act upon the oocyte to promote maturation, allowing for ovulation to occur. Notably, MMPs appear to be important only for ovarian steroid production, offering us a novel target for specifically regulating steroidogenesis in the ovary. Accordingly, in cycling and superovulated mice, we were able to show that treatment with the broad-spectrum MMP inhibitor Galardin in vivo, decreased ovarian steroid production without affecting adrenal steroidogenesis. Given these findings we propose that MMP inhibitors may be useful to specifically down-regulate excess ovarian steroid production in diseases such as polycystic ovarian syndrome (PCOS), the leading cause of infertility in women of reproductive age.