Role of the epidermal growth factor network in ovarian follicles.

The LH surge causes major remodeling of the ovarian follicle in preparation for the ovulatory process. These changes include reprogramming of granulosa cells to differentiate into luteal cells, changes in cumulus cell secretory properties, and oocyte maturation. This review summarizes published data in support of the concept that LH stimulation of ovarian follicles involves activation of a local epidermal growth factor (EGF) network. A model describing this property of LH signaling and its branching to other signaling modules is discussed. According to this model, LH activation of mural granulosa cells stimulates cAMP signaling, which, in turn, induces the expression of the EGF-like growth factors epiregulin, amphiregulin, and betacellulin. These growth factors function by activating EGF receptors in either an autocrine/juxtacrine fashion within the mural layer, or they diffuse to act on cumulus cells. Activation of EGF receptor signaling in cumulus cells, together with cAMP priming, triggers oocyte nuclear maturation and acquisition of developmental competence as well as cumulus expansion. This model has important implications for ovarian physiology and for the development of new strategies for the pharmacological control of ovulation and for gamete maturation in vitro.