Grant: Operating Grant

Women are born with finite numbers of oocytes (immature eggs), and continually lose them with age, thus limiting their reproductive life span. When the oocyte reserve reaches a threshold, hormones are not properly produced by the ovary; and menopause ensues. The oocyte reserve in mammals is limited because all germ cells (the precursor of oocytes) stop proliferation and enter meiosis (a specific cell division which produces the haploid genome) to become oocytes in fetal life, and, in addition, more than half of the initial oocyte population is eliminated before birth. During this period, paternal and maternal homologous chromosomes pair, synapse and recombine; these events are essential for securing proper chromosome segregation in oocytes and generating genetic diversity in the offspring. We hypothesize that a failure in meiotic synapsis or recombination (asynapsis) in oocytes initiates a cascade of cellular events leading to elimination of oocytes carrying asynapsis, thus minimizing the risk of aneuploidy (abnormal chromosome number) in embryos. Aneuploidy is the major cause of embryonic death, stillborn, and live-born infants with chromosomal anomalies. Consequently, problems with proper oocyte elimination during Meiotic Prophase I could influence a woman's fertility and the health of her offspring. To test our hypothesis, we propose (1) to delineate the mechanism regulating the apoptotic (programmed cell death) pathway leading to oocyte elimination, (2) to identify the mechanism by which persistent chromosome asynapsis leads to apoptotic elimination of oocytes, and (3) to evaluate the chromosomal integrity of oocytes that survive when apoptotic elimination is circumvented. The results of these studies will clarify the role of oocyte elimination during normal ovarian development and provide insight regarding the genetic mechanisms that underlie an increased risk of aneuploidy.