Gonadotropin-induced Steroidogenesis and Downstream Signals Leading to Oocyte Maturation



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The Hammes laboratory is interested in understanding the process of steroid-mediated oocyte maturation. This includes examining both steroid production and steroid signaling. In these studies, gonadotropin-induced steroid production was examined in the gonads using mouse models, as well as steroid-induced oocyte maturation in frog models. cAMP signaling is known to be important for steroid production, but further downstream pathways were not well characterized. These studies illuminate other downstream signaling pathways triggered by luteinizing hormone (LH) that regulate steroid production in the testes using Leydig cells, which are the primary steroidogenic cells in the testes. A novel downstream pathway was found involving epidermal growth factor receptor (EGFR) transactivation, downstream mitogen-activated protein kinase (MAPK) and steroidogenic acute regulatory protein (StAR) activation that was essential for short, but not long-term LH-induced steroidogenesis in MLTC-1 and primary mouse leydig cells. Despite this discrepancy in vitro, EGFR signaling was required in vivo for testicular testosterone production. To study the effects of steroids on oocyte maturation, the Xenopus laevis frog model was used. It has been shown that G-beta gamma, as well as other signals, keep the oocyte in meiotic arrest. Steroids block this constitutive signal, leading to oocyte maturation. To directly measure rapid changes in G-beta gamma signaling in oocytes, G-beta gamma sensitive-inward rectifying potassium channel currents (GIRKS) were exogenously expressed in Xenopus oocytes. Adding testosterone, the physiologic mediator of oocyte maturation in Xenopus, decreased the G-beta gamma mediated signal. This happened rapidly supporting the well known idea that maturation is a transcription-independent process. It was also seen that the classical androgen receptor (AR) was being used for this process. When the AR was knocked down, testosterone could only decrease GIRK signal at higher concentrations. This showed that testosterone is working, at least partially, through the AR. These studies may help elucidate novel targets for polycystic ovary syndrome (PCOS), which is characterized by excess androgen due to improper steroid production.

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