Reproductive lifespan in women spans puberty to the menopause. However, in about 1-2% of women, early menopause occurs, and this has negative health consequences, including increases in heart disease, bone loss, hot flashes, or even early death. The number of oocytes found in the non-growing pool of ovarian follicles (the ovarian reserve), is currently thought to largely determine the age at the menopause. Thus, premature menopause arises if oocytes are dysfunctional or damaged. Mouse models demonstrate that oocyte-specific transcription factors are required for the development of oocytes within the ovarian reserve. Deletion of these genes, which includes newborn ovary homeobox gene (Nobox), causes female sterility and premature loss of oocytes in mice. Furthermore, women with premature ovarian failure frequently have mutations in NOBOX. Even though NOBOX is required for oocyte development, there is little to no information on how NOBOX function is regulated. In silico analysis of NOBOX identified SUMOylation as a potential regulatory mechanism. SUMOylation is a posttranslational modification that controls protein stability, localization, and activity, particularly for transcription factors. However, the function of SUMOylation during intraovarian oocyte development is not known. Therefore, we generated a novel oocyte-specific knockout of Ubc9, which is a central component of the SUMOylation cascade. Loss of Ubc9 in oocytes beginning at the primordial follicle stage caused female sterility and a full depletion of the oocyte reserve in young adult mice. Preliminary data indicate that loss of SUMOylation affects NOBOX function and the phenotype manifests at the primary to secondary follicle stage.
The Aims of this project designed to (1) determine why there are defects in oocyte development at the primary to secondary follicle stage and (2) elucidate how SUMOylation alters oocyte- specific transcription factor function, resulting in altered gene expression and oocyte death/survival. The results from these Aims will provide insight into the regulation of key oocyte-specific transcription factors and the genesis of premature ovarian failure. Importantly, these studies will establish SUMOylation as an essential process in intraovarian oocyte development.
Infertility is a health issue for 15% of the general population with women representing approximately half of those cases. Disrupting normal cellular processes that control oocyte development can lead to germ cell loss, aneuploidy, or other chromosomal defects that contribute to infertility, premature menopause, pregnancy loss, or congenital defects. The goal of these studies is to determine how SUMOylation, a post-translational protein modification, is required in the generation of oocytes and how SUMOylation regulates the activity of factors essential for oocyte health and development.
|Monsivais, Diana; Matzuk, Martin M; Pangas, Stephanie A (2017) The TGF-? Family in the Reproductive Tract. Cold Spring Harb Perspect Biol 9:|