Defects in oocyte development are fundamental to the etiology of benign and malignant spontaneous ovarian teratomas in women. Moreover, since clinical therapies targeting oocyte meiosis for fertility control might increase the risk of teratoma development, it is critical to devise strategies to understand what these risks are and how they might be avoided. The overall objective of the proposed experiments is to determine the cellular, physiological, and molecular abnormalities underlying oocyte defects that lead to teratoma formation using mice as animal models. Although teratomas are generally rare in mice, they occur commonly in strain LT/Sv and related strains. In these mice, teratomas are derived from oocytes that undergo spontaneous parthenogenetic activation and development within the ovary. A meiotic cell cycle abnormality resulting in precocious arrest at metaphase I is a necessary but insufficient antecedent to spontaneous parthenogenetic activation.
The specific aims of this proposal are to define mechanisms of spontaneous parthenogenetic activation that initiate teratoma development in strain LT mice. The hypothesis to be tested in Specific Aim 1 is that spontaneous increases in cytosolic free calcium occur in metaphase I-arrest oocytes of strain LT mice and, once maturing oocytes become calcium-sensitive and activation-competent, the relative increases in cytosolic free calcium concentrations induce spontaneous parthenogenetic activation. Granulosa cells associated with the oocyte promote parthenogenetic activation in LT mice by a gap junction-independent mechanism. Therefore, Specific Aim 2 is to test the hypothesis that cumulus cells promote spontaneous activation of LT oocytes by secreting one or more factors that induce intracellular mobilization of free calcium in oocytes.
Specific Aim 3 is to identify candidate genes that participate in metaphase I arrest and spontaneous parthenogenetic activation. The chromosomal locations of genes producing metaphase I arrest and spontaneous parthenogenetic activation will be mapped with the goal of identifying and testing candidate genes that produce these abnormal phenotypes.
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