Targeted expression of Bcl-2 in mouse oocytes inhibits ovarian follicle atresia and prevents spontaneous and chemotherapy-induced oocyte apoptosis invitro

Members of the Bcl-2 family serve as central checkpoints for cell death reg ulation, and overexpression of Bcl-2 is known to inhibit apoptosis in many cell types. To determine whether targeted expression of Bcl-2 could be used to protect female germ cells from apoptosis, we generated transgenic mice expressing fully functional human Bcl-2 protein only in oocytes. Transgenic mice were produced using a previously characterized 480-bp fragment of the mouse zona pellucida protein-3 (ZP3) gene 5'-flanking region to direct ooc yte-specific expression of a human bcl-2 complementary DNA. Immunohistochem ical analyses using a human Bcl-2-specific antibody showed that transgene e xpression was restricted to growing oocytes and was not observed in the sur rounding ovarian somatic cells or in any other nonovarian tissues. Histomor phometric analyses revealed that ovaries collected from transgenic female m ice possessed significantly fewer atretic small preantral follicles compare d with wild-type sisters, resulting in a larger population of healthy matur ing follicles per ovary. However, the number of oocytes ovulated in respons e to exogenous gonadotropin priming and the number of pups per litter were not significantly different among wild-type vs. transgenic female mice. Non etheless, oocytes obtained from transgenic mice and cultured in vitro were found to be resistant to spontaneous and anticancer drug-induced apoptosis. We conclude that targeted expression of Bcl-2 only in oocytes can be achie ved as a means to convey resistance of the female germ line to naturally oc curring and chemotherapy-induced apoptosis.