THE GENES OF CELL-DEATH AND CELLULAR-SUSCEPTIBILITY TO APOPTOSIS IN THE OVARY - A HYPOTHESIS

Recent advances in the field of cell death, primarily derived from gen e-transfer experiments and manipulation of tumor cell lines in vitro, have identified key genes responsible for determining whether or not a given cell will initiate apoptosis, However, comparatively less is kn own of the role that the products of these genes play in physiological settings of cell death, In the ovary, a tremendous level of normal ce ll death takes place in the germline throughout the later stages of fe tal development, This process is responsible for setting the absolute number of oocytes ('eggs') available for subsequent development and ov ulation during adult life, Interestingly, death remains the fate of th e vast majority of oocytes that survive the waves of attrition during fetal life and are endowed in the post-natal ovary as primordial folli cles, This pool of oocytes is lost indirectly as a consequence of the death of the somatic (granulosa) cells that, in the case of a small pe rcentage of the total follicles, support and nourish the oocyte until its release at ovulation, Due to the magnitude of cell death that occu rs normally within the female gonad during both fetal development and post-natal life, the ovary has proven to be an excellent model to stud y the role of cell death genes in a physiological setting of endocrine -regulated apoptosis, It is now known that a diverse spectrum of pro a nd anti apoptosis susceptibility genes, including members of the bcl-2 and CASP(ced-3/lce) gene families, are expressed in germ cells and/or somatic cells of the ovary, Many, but not all, of these genes are reg ulated by specific survival factors, such as gonadotropins and growth factors, and changes in the temporal patterns of cell death gene expre ssion suggest an intimate association exists between the products of t hese genes and activation of cellular suicide, Moreover, pathological oocyte destruction, such as that triggered by exposure of female germ cells to chemotherapeutic compounds or environmental toxicants, may al so be dependent upon gene-driven apoptosis, As such, this review will discuss data supporting the hypothesis that the susceptibility of ovar ian cells to death induction is dependent upon the pattern of cell dea th gene expression occurring within those cells prior to and/or concom itant with receipt of the stimulus for apoptosis, Elucidation of the r elationship between germ cell loss and cell death genes may allow futu re intervention into the process of oocyte depletion associated with n ormal and pathophysiological reproductive senescence.