Species: mouse
Mutation name: None
type: null mutation
fertility: fertile
Comment: SSR 2010 abstract 160. Deletion of the BH3-only Gene puma Protects Oocytes from Apoptosis and Preserves Fertility Following Anti-Cancer Therapy-Induced DNA Damage. Karla J. Hutt, Jeffrey B. Kerr, Ewa M. Michalak, Michele Cook, Clare L. Scott, Andreas Strasser, and Jock K. Findlay. Prince Henry?s Institute of Medical Research, Clayton, VIC, Australia; Monash University, Clayton, VIC, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia Anti-cancer therapy-induced DNA damage can cause primordial follicle oocyte depletion resulting in female sterility. p63 is the predominant p53 family member expressed in primordial follicle oocytes and it is essential for their death following DNA damage. While p53 is known to exert pro-apoptotic effects in part through transcriptional induction of the BH3-only Bcl-2 family members, Puma and Noxa, it is not clear how p63 mediates apoptosis in a physiological setting. We used genetargeted (?knock-out?) mice to investigate the hypothesis that Puma and Noxa are critical down-stream apoptosis effectors for p63 following DNA damage in primordial follicle oocytes. Postnatal day (PN) 5 puma-/-, noxa-/-, puma-/-noxa-/-, or wild-type (wt) mice (n=4-8/genotype) were exposed to c-irradiation (0.45 Gy) and ovaries were harvested at PN10 for follicle enumeration. c-Irradiation resulted in complete destruction of the primordial follicle pool in wt mice. In striking contrast, approximately 16% 6 3% of primordial follicles were protected from c-irradiationinduced apoptosis in mice lacking Puma, and even more primordial follicles (52% 6 6%) were rescued from apoptosis in mice lacking both Puma and Noxa (p,0.001 compared to wt). We next investigated whether resistance to DNA damage-induced apoptosis afforded to primordial follicle oocytes by loss of Puma could preserve fertility. Puma-/- mice were c-irradiated (0.45 Gy) at PN5 and breeding studies commenced 45 days later. Remarkably, 13 out of 16 c-irradiated puma-/- females produced healthy offspring when mated with non-irradiated wt males, whereas all (5/ 5) c-irradiated wt females were infertile. These findings indicate that the puma-/- primordial follicle oocytes rescued from c-irradiation-induced apoptosis are functionally robust and capable of giving rise to normal healthy offspring. The inhibition of p63-mediated apoptosis in primordial follicle oocytes, through blockade of Puma, has profound implications for the design of therapeutic approaches for the prevention of infertility following anti-cancer treatment.