SCG2, MRO, and SHOX2 Expression, Regulation, and Function During Ovulation in Humans

Defects in ovulation are a contributing factor to the prevalence of infertility, where 25% of all cases of female infertility are attributed to aberrant or irregular ovulation. Thus, understanding the mechanisms that control ovulation are critical to reduce infertility rates, refine infertility treatment protocols, decrease the costs associated with infertility, and benefit the overall health care of women. The periovulatory period is an essential window of the ovarian control of ovulation and fertility, where the luteinizing hormone (LH) surge upregulates mediators of ovulation that promote oocyte release and corpora lutea formation. Previous studies conducted in rodents have reported the discovery of vital ovulatory mediators downstream of the LH surge; yet, there is a paucity of data concerning the translational evidence of these mediators in human ovulatory biology. Further, the existence of additional mediators of ovulation is unknown. Our preliminary data are the first to show that secretogranin II (SCG2) mRNA levels are upregulated in response to human chorionic gonadotropin (hCG; analogous to LH) treatment in human and mouse granulosa cells in vitro and in vivo, respectively. These data suggest that SCG2 may play a substantial role during the periovulatory period to aid in ovulation. In non-ovarian systems, SCG2 is involved in the formation of secretory vesicles, or SCG2 can be cleaved to 3 peptides: secretoneurin, EM66, and manserin. These secreted peptides are involved in the inflammatory chemotaxis of leukocytes and angiogenesis, both of which are requisite events for ovulation and fertility. However, outside of our preliminary data, the roles of SCG2 and its derived peptides in ovarian function and ovulation have not been studied. The goal of the proposed research is to elucidate the periovulatory actions of SCG2 in the ovary. We propose to use human, non-human primate, and mouse ovarian samples to test the hypothesis that SCG2 is an LH-inducible factor that promotes the vital angiogenic, immunological, and secretory transformations necessary for successful ovulation. To test this, we will determine the characterization (Specific Aim 1), regulation (Specific Aim 2), and function (Specific Aim 3) of SCG2 across species and across defined intervals during the periovulatory period in vivo and in vitro. The characterization experiments will identify the induction of SCG2 and its derived peptides during the periovulatory period across species, the regulation experiments will elucidate the mechanism by which SCG2 is induced by LH, and the function experiments will define the role of SCG2 and its derived peptides in the ovulatory process. Only by achieving these aims will we be able to promote or inhibit the events controlled by SCG2 during the periovulatory period, which will facilitate fertility or act as a contraceptive agent. Further, the evidence obtained from the utilization of human samples will enhance our understanding of the translational events associated with ovulation.