In the mammalian ovary, progressive activation of primordial follicles from the dormant pool serves as the source of fertilizable ova. Menopause, or the end of female reproductive life, occurs when the primordial follicle pool is exhausted. However, the molecular mechanisms underlying follicle activation are poorly understood. We provide genetic evidence that in mice lacking PTEN (phosphatase and tensin homolog deleted on chromosome 10) in oocytes, a major negative regulator of phosphatidylinositol 3-kinase (PI3K), the entire primordial follicle pool becomes activated. Subsequently, all primordial follicles become depleted in early adulthood, causing premature ovarian failure (POF). Our results show that the mammalian oocyte serves as the headquarters of programming of follicle activation and that the oocyte PTEN-PI3K pathway governs follicle activation through control of initiation of oocyte growth.

Heterochromatin in aging stem cells: Analysis of human aging syndromes, such as Werner syndrome (WS), may lead to greater understanding of both premature and normal aging. Zhang et al. generated isogenic WS-specific human embryonic stem cell lines (see the Perspective by Brunauer and Kennedy). WS-mesenchymal stem cells displayed features characteristic of premature aging, including heterochromatin disorganization. WRN protein thus functions in the maintenance of heterochromatin, and heterochromatin alterations may represent a driving force of human aging. Science , this issue p. 1160 ; see also p. 1093