This proposal is part of an IRPG project whose overall goal is to define the genetic, developmental and endocrinological bases of tumorigenesis in germ cell and granulosa cells. This project focuses on the mechanisms of ovarian teratocarcinogenesis and, like the companion IRPG projects, will exploit unique mouse models for spontaneous ovarian tumorigenesis and integrate complementary skills and resources in the areas of genetics, developmental biology and endocrinology to promote efficiency and maximize prospects for success. Defects in oocyte development are fundamental to the etiology of both benign and malignant ovarian teratomas in women. This study seeks to determine the defects underlying the parthenogenetic activation of oocytes, the initial cellular lesion that results in teratoma formation. A unique strain of mice, strain LT/Sv, in which the spontaneous incidence of ovarian teratomas is approximately 30%, will be utilized. Teratomas in LT/Sv mice are derived from oocytes that become parthenogenetically activated within the ovarian follicles. In addition to the high frequence of spontaneous parthenogenetic activation, LT/Sv oocytes are atypical because many become arrested at metaphase I when normal oocytes progress to metaphase II. Experiments proposed in this application will test the hypothesis that meiosis in LT/Sv oocytes is abnormal due to an aberrant pattern of activity of a key cell cycle control molecule, the cdc2 kinase. It is proposed that high cdc2 kinase activity maintains metaphase I arrest in LT/Sv oocytes and that the oocytes' companion somatic cells mediate this effect. Moreover, it is postulated that the arrest in the progression of the nuclear events of oocyte maturation does not affect the progression of important events of cytoplasmic maturation that are essential for egg activation and embryo development. Thus, the eventual decline in the cdc2 kinase activity in LT/Sv oocytes occurs in a cytoplasmic environment appropriate to metaphase II rather than metaphase I oocytes (as it would in normal circumstances), and results in parthenogenetic activation as well as the completion of the first meiotic division. Unique oocyte culture systems developed by the PI, and measurements of cdc2 kinase activity in oocytes will be utilized to address these hypotheses. The experiments proposed here will determine whether abnormalities in the regulation of cdc2 kinase activity in LT/Sv oocytes are critical for the primary events in ovarian teratoma development, specifically, the abnormalities in meiosis and subsequent parthenogenetic activation. Furthermore, they will determine the role of the oocytes' companion somatic cells, the granulosa cells, in these processes. Finally, these studies may demonstrate that somatic cell-to- oocyte interactions that alter the dynamics of the cdc2 kinase activity initiate the processes culminating in the formation of commonly occurring ovarian tumor, the teratoma. In a larger context, the objective of these experiments, combined with Dr. Nadeau's genetic studies, described in the accompanying IRPG proposal, is to identify key genes and factors that regulate the development of the atypical phenotype of LT/Sv oocytes, to develop new protocols to identify those at risk, and to devise strategies for prevention.
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