Strict regulation of somatic cell proliferation characterizes the onset of ovarian development. (#15)
Formation of the ovary is initiated during mid-gestation development in the mouse and lays the foundation for ongoing female fertility. The early stages of ovarian development are poorly understood at the cellular and molecular levels. Signalling through Wnt b-Catenin interacts with an apparently independent pathway modulated by the transcription factor FoxL2 to promote ovarian development. This results in formation of oogonial nests surrounded by supporting somatic cells, and the entry of the early oocytes into meiosis. Testis specification, which is understood in more detail, requires expression of the testis-determining factor SRY and the related transcription factor SOX9. This drives proliferation of the Sertoli cells through action of the growth factors Fgf9 and Activin. Formation of the testis promotes male germ cell specification and entry of the germ cells into mitotic arrest, a process that involves expression of the cell cycle inhibitor p27KIP1.
In this study we demonstrate that ovarian development is characterized by early entry of ovarian somatic cells into mitotic arrest, strong upregulation of the cell cycle inhibitor p27KIP1 and expression of FoxL2. Loss of FoxL2 leads to a significant reduction in p27KIP1, but mitotic arrest is retained. However, several growth factors modulate this process, leading to repression of p27KIP1 and proliferation of the ovarian soma. These data provide novel insights into the cellular and molecular events that underpin the earliest stages of ovarian development. Greater understanding of these processes is likely to yield insights into female infertility, the occurrence of premature ovarian failure and potentially the formation of ovarian tumours.