The Release of EGF Domain from EGF-like Factors by a Specific Cleavage Enzyme Activates the EGFR-MAPK3/1 Pathway in Both Granulosa Cells and Cumulus Cells During the Ovulation Process

In mammalian preovulatory follicles, LH stimulation induces the ovulation process, including follicular wall rupture, granulosa cell luteinization, cumulus cell expansion and meiotic maturation of the oocyte. The receptor for LH (LHCGR) is expressed mostly in granulosa cells of preovulatory follicles, and is rarely expressed in cumulus cells or oocytes. The expression level in granulosa cells dramatically decreases after ovulation stimuli. Thus, a potent factor(s) secreted by granulosa cells is required to stimulate not only granulosa cells via an autocrine manner but also cumulus cells and/or oocytes via a paracrine pathway. Recent reports showed that granulosa cells and cumulus cells express EGF-like factors that activate the EGF receptor (EGFR)-mitogen-activated protein kinase3/1 (MAPK3/1) (also known as extracellular signal-regulated kinase1/2 (ERK1/2)) pathway in both cell types. EGF-like factors are composed of a signal sequence, transmembrane domain and EGF domain, suggesting that release of the EGF domain by a specific enzyme is essential for interaction with the EGFR to induce the ovulation process. In our studies, TACE/ADAM17, which is known to be a proteolytic enzyme of EGF-like factors in many types of tissue, was found to be expressed in FSH/LH-stimulated granulosa cells and cumulus cells together with activation of the EGFR-MAPK3/1 pathway. When TACE/ADAM17 activity was decreased by a specific inhibitor or si RNA technique, granulosa cell luteinization, cumulus expansion and oocyte maturation were suppressed in an in vitro culture. Thus, TACE/ADAM17 is one of the key genes expressed in both granulosa cells and cumulus cells for induction of the ovulation process.