Classical steroid receptors mediate many transcription-independent (nongenomic) steroid responses in vitro. A major problem in this field has been to justify the biological significance of these nongenomic processes, since dissecting the relative importance of genomic versus nongenomic steroid receptor- mediated signaling is difficult. To circumvent these concerns, our laboratory studies steroid-induced maturation, or meiotic resumption, of oocytes. Oocyte maturation is an important, biologically relevant, steroid-mediated phenomenon that is well-accepted to occur completely independent of transcription. In fact, transcription is silenced during oocyte maturation, and many steroid-induced cytoplasmic signals actually occur in enucleated frog oocytes. This application is a competitive renewal for our R01, """"""""Nongenomic Signaling by Steroids at the Cell Membrane."""""""" For the first grant we proposed to study steroid-triggered meiosis in Xenopus laevis oocytes. In the past 4 years, we: 1) showed that androgens are the physiologic mediators of Xenopus oocyte maturation; 2) implicated classical androgen receptors (ARs) as mediators of androgen-triggered maturation; 3) described a """"""""release of inhibition"""""""" mechanism whereby steroids attenuate constitutive G protein signaling that holds cells in meiotic arrest; 4) showed that the Modulator of Nongenomic Actions of steroid Receptors (MNAR) links the AR to Gbeta; 5) began characterization of Xenopus GPRS, which participates in maintaining meiotic arrest; 6) demonstrated a role for Paxillin in regulating steroid-triggered signals; and 7) showed that nongenomic steroid-mediated signaling is conserved from frogs to mice.
The aims of this competitive renewal, """"""""Nongenomic Steroid Signaling in Oocytes,"""""""" are to build upon our results from the previous funding period. We will: 1) use mouse knockout models to examine the importance of classical steroid receptors in regulating steroid-triggered oocyte maturation; 2) characterize the role of MNAR as a regulator of oocyte maturation and as a general modulator of G protein signaling; and 3) elucidate the role of Paxillin in regulating both oocyte maturation and MAPK signaling. These studies should lead to significant contributions in the fields of steroid receptor and G protein-mediated signaling, MAPK signaling and protein translation, as well as in the fields of meiosis and ovarian function.
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