Molecular genetic basis of sex-specific differentiation of germ cells

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SUMMARY The oocyte, when fertilized has the capacity to generate every cell in an organism. Efforts to understand and harness the reprogramming potential of this “mother of all stem cells” gave rise to today's stem cell research field. Despite their unique developmental potential, oocytes are highly specialized and differentiated cells. A key step in oocyte development is the transition from a mitotic germline stem cell that in most animals is specified prior to sexual differentiation to a meiotic germ cell that develops as an oocyte in females or sperm in males. Development of the oocyte is a prolonged developmental time-period characterized by highly conserved periods of meiotic activity, arrest, and substantial oocyte growth and maturation to yield a fertilizable egg. Before the first meiotic division the oocyte stops producing new RNAs. Consequently, control of programs vital to egg production and fertility rely heavily on regulation by proteins, called RNA binding proteins, that bind to RNAs and regulate their activity. Reproductive success relies on proper establishment and maintenance of sexual identity. Defects in germ cell differentiation can lead to infertility or germ cell tumors. Identifying RNA binding protein targets, and determining how they act in oocyte development is essential to fill the large gaps in our understanding of the mechanisms and molecular pathways that preserve female sex identity of the germ cells and fertility. Our long- term goal is to determine the mechanisms that regulate sex-specific programing of germ cells. We utilize the zebrafish, a powerful vertebrate genetic system to examine the mechanisms and identify genes that are crucial for successful fertility, maintenance of germ cell identity and ovarian reserve, and thus may define new molecular pathways that, when defective, can result in reduced fertility, premature ovarian insufficiency, polycystic ovary syndrome, or cancers in humans. In this proposal, mechanisms regulating sex-specific differentiation of germ cells and fertility will be tested using a combination of genetic loss of function and over expression approaches.