Characterization of cell fate determination in oocyte differentiation and oocyte development in the mouse ovary
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The production of the oocyte in mammals begins in the fetal stage with the formation of primordial germ cells (PGCs). PGCs differentiate through the process of oocyte differentiation to become primary oocytes. After the emergence of primary oocytes, the oocytes become quiescent and enclosed by somatic follicle cells to form the ovarian reserve. The ovarian reserve forms through a highly conserved process in mammals and serves as the only resource to sustain and prolong female reproductive life. Primary oocytes are activated periodically from the ovarian reserve when puberty occurs. Once a primary oocyte is activated in the ovary, it has two fates available to it, continue through oocyte development and potentially be ovulated or face cell death. In my master's thesis I explore the cellular mechanisms of the mouse ovary spanning oocyte differentiation to oocyte development. In chapter one, I investigate oocyte differentiation, specifically cell fate determination in fetal gametogenesis. During mammalian fetal gametogenesis, both male and female germ cells are connected via intercellular bridges yet experience major differences in cell fate determination. In mouse fetal testes, male germ cells arrest in G0/G1 after embryonic day (E)14.5 and differentiate into gonocytes postnatally. In contrast mouse female germ cells enter meiosis after E14.5 and initiate oocyte differentiation. During oocyte differentiation, two fates are possible, ~80 percent of the germ cells donate organelles and undergo cell death; ~20 percent of the germ cells collect organelles from sister germ cells and become primary oocytes. Due to the small percentage of germ cells that become primary oocytes, this led us to investigate the differences in cell fates between female and male germ cells using single cell RNA sequencing. The findings highlight key features in female and male germ cell transcriptomics. This data helps us understand cellular mechanism differences in female and male germ cell populations and how it relates to differential cell fates. In chapter two, I investigate oocyte development, specifically whether quiescent primary oocytes experience cellular senescence and non-apoptosis cell death in the mouse ovary, a process that may lead to primary ovarian insufficiency (POI) and physiological ovarian aging. Cellular senescence is characterized by cell cycle arrest and production of the senescence associated secretory phenotype (SASP) associated with tissue aging. The activation of primary oocytes from the ovarian reserve is an irreversible process that forces the oocytes to develop via folliculogenesis or undergo cell death. In this project we used a mouse model with POI phenotypes caused by Pten depletion specifically in the oocyte. We examined quantitatively cellular senescence and cell death (apoptosis and ferroptosis) in 2 weeks and 4 weeks old mutant mouse ovaries, when primary oocyte loss take place. Our data demonstrated that overactivation of primary oocytes contributes to a reduction in the ovarian reserve in mutant ovaries; and an increased number of senescent primary oocytes were found in mutant ovaries as well. Although it appeared in a low number, it was found that all primary oocytes that undergo ferroptosis were senescent. This data drives what is known about cellular mechanisms in oocytes further by providing quantitative results of follicle loss, cellular senescence, and cell death markers in the primary oocyte.
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M.S.