MAPK3/1 (ERK1/2) in Ovarian Granulosa Cells Are Essential for Female Fertility

Regulating Oocyte Maturation Understanding exactly how ovarian follicles mature to generate fertile eggs is key to many aspects of fertility treatment. When the pituitary surge of luteinizing hormone (LH) binds to its receptor on granulosa cells of preovulatory follicles, a cascade of signaling events triggers granulosa cells to become luteal cells and the oocyte to resume meiosis. Fan et al. (p. 938; see the Perspective by Duggavathi and Murphy), using the mouse as a model system, targeted disruption of the kinases ERK1 and ERK2 selectively in granulosa cells. The kinases were essential in vivo mediators of LH induction of ovulation and luteinization. Targeted disruption of the kinases derails the molecular events that mediate induction of female reproductive development. A surge of luteinizing hormone (LH) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Because the signaling molecules RAS and ERK1/2 (extracellular signal–regulated kinases 1 and 2) are activated by an LH surge in granulosa cells of preovulatory follicles, we disrupted Erk1/2 in mouse granulosa cells and provide in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization. In addition, biochemical analyses and selected disruption of the Cebpb gene in granulosa cells demonstrate that C/EBPβ (CCAAT/Enhancer-binding protein–β) is a critical downstream mediator of ERK1/2 activation. Thus, ERK1/2 and C/EBPβ constitute an in vivo LH-regulated signaling pathway that controls ovulation- and luteinization-related events.

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