Apoptosis and DNA repair: critical regulators of oocyte number and quality (#85)
Primordial follicles are the most abundant and long-lived form of female gamete found in the post-natal ovary and they the source of all mature oocytes for ovulation. An adequate supply of healthy primordial follicles is critical for ensuring female health and fertility, but surprisingly, the genes/proteins that regulate primordial follicle number and quality are largely unknown. We have discovered that neonatal mice deficient in the pro-apoptotic BH3-only proteins Puma or Bmf have an extraordinary oversupply of primordial follicles when compared to wild type (WT) mice. This finding indicates that Puma and Bmf are responsible for initiating cell death during fetal oogenesis and thereby determine the number of primordial follicles available to sustain fertility throughout reproductive life. We are now determining the exact stages of oogenesis during which Puma and Bmf initiate cell death and are investigating the exciting possibility that the fertile lifespan may be extended by increasing the number of primordial follicles initially established in the ovary. We have also shown that, in the post-natal ovary, the DNA-damage induced apoptosis of primordial follicle oocytes is mediated by transcriptional activation of Puma by TAp63. In WT mice, whole body γ-irradiation (0.45 Gy) resulted in death of all primordial follicles and infertility. In contrast, ~16% of primordial follicles were protected from apoptosis in Puma-/- females, and remarkably these irradiated mice produced healthy pups when mated with WT untreated males. We show that primordial follicles rescued from apoptosis are able to repair their damaged DNA so that oocytes of sufficient quality are available to produce healthy offspring. Thus, while apoptosis may be one mechanism for protecting the female germ line, it is not essential for oocyte quality. These studies provide support for the development of novel adjuvant therapies aimed at preventing the death of oocytes (and ensuing infertility and premature menopause), which is a common side effect of DNA damaging anti-cancer treatment.