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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA062392-06
Application #
6124502
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Mietz, Judy
Project Start
1994-09-01
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
6
Fiscal Year
2000
Total Cost
$369,542
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Viveiros, Maria M; O'brien, Marilyn; Eppig, John J (2004) Protein kinase C activity regulates the onset of anaphase I in mouse oocytes. Biol Reprod 71:1525-32
Su, You-Qiang; Denegre, James M; Wigglesworth, Karen et al. (2003) Oocyte-dependent activation of mitogen-activated protein kinase (ERK1/2) in cumulus cells is required for the maturation of the mouse oocyte-cumulus cell complex. Dev Biol 263:126-38
Viveiros, Maria M; O'Brien, Marilyn; Wigglesworth, Karen et al. (2003) Characterization of protein kinase C-delta in mouse oocytes throughout meiotic maturation and following egg activation. Biol Reprod 69:1494-9
Su, You-Qiang; Wigglesworth, Karen; Pendola, Frank L et al. (2002) Mitogen-activated protein kinase activity in cumulus cells is essential for gonadotropin-induced oocyte meiotic resumption and cumulus expansion in the mouse. Endocrinology 143:2221-32
Matzuk, Martin M; Burns, Kathleen H; Viveiros, Maria M et al. (2002) Intercellular communication in the mammalian ovary: oocytes carry the conversation. Science 296:2178-80
Su, You-Qiang; Eppig, John J (2002) Evidence that multifunctional calcium/calmodulin-dependent protein kinase II (CaM KII) participates in the meiotic maturation of mouse oocytes. Mol Reprod Dev 61:560-9
Viveiros, M M; Hirao, Y; Eppig, J J (2001) Evidence that protein kinase C (PKC) participates in the meiosis I to meiosis II transition in mouse oocytes. Dev Biol 235:330-42
Eppig, J J; Wigglesworth, K; Hirao, Y (2000) Metaphase I arrest and spontaneous parthenogenetic activation of strain LTXBO oocytes: chimeric reaggregated ovaries establish primary lesion in oocytes. Dev Biol 224:60-8
Hirao, Y; Eppig, J J (1999) Analysis of the mechanism(s) of metaphase I-arrest in strain LT mouse oocytes: delay in the acquisition of competence to undergo the metaphase I/anaphase transition. Mol Reprod Dev 54:311-8
Ruan, B; Watanabe, S; Eppig, J J et al. (1998) Sterols affecting meiosis: novel chemical syntheses and the biological activity and spectral properties of the synthetic sterols. J Lipid Res 39:2005-20

Showing the most recent 10 out of 19 publications