Co-ordinated regulation of ovarian follicle assembly by Activin A and FoxL2

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Female reproductive lifespan is established during fetal life through the formation of a cohort of primordial follicles in the developing ovary. Primordial follicles consist of an egg (oocyte) surrounded by a layer of pre-granulosa cells, which support, maintain and control the growth of the oocyte. Women are born with a finite number of follicles which decline in number throughout life, and no new follicles are formed after birth. The menopause occurs when the follicular reserve is exhausted, which normally happens around the age of 50. However, in 1% of women the menopause occurs before the age of 40, a condition known as premature ovarian insufficiency (POI). In addition to being a devastating diagnosis for women yet to complete their families, POI is associated with significant post-menopausal health risks, such as osteoporosis and cardiovascular disease. Furthermore, as societal trends move increasingly towards starting families later in life, and the supply and quality of oocytes in the ovary declines with age, the number of women experiencing sub-fertility is likely to rise. Despite the critical importance of the follicle formation process in establishing reproductive lifespan in humans, and other mammals (such as livestock species), we know very little about how the stock of follicles is formed in the fetal ovary. Improving our knowledge of this fundamental process is essential if we are to investigate how genetic, environmental or lifestyle factors can disrupt follicle formation and curtail reproductive lifespan. The cell to cell signalling molecule Activin A (ActA) is a possible key regulator of follicle formation. Elevated ActA signalling in fetal/neonatal mouse ovaries results in the formation of greater numbers of primordial follicles. The mechanism by which this occurs is unclear, but is likely to involve changes to pre-granulosa cell number or behavior, as ActA only signals to this cell type in the developing ovary. Pre-granulosa cells also express a protein called FoxL2, which activates genes important for ovarian development. In humans, mutations in the FOXL2 gene cause POI, infertility and granulosa cell tumours (a rare type of ovarian cancer). In mice, pre-granulosa cells that lack FoxL2 cannot function correctly, and so fail to form follicles (or form follicles that cannot mature). In the pituitary gland, ActA and FoxL2 work together to activate genes that are required for cells to respond to, and produce, reproductive hormones, and a similar FoxL2/ActA interaction activates genes in the granulosa cells of the adult ovary. Whether ActA and FoxL2 work together to regulate pre-granulosa cell function and follicle formation in the fetal ovary is not known, however. The aim of this project is to address this question, using the neonatal mouse ovary and human pre-granulosa cells as models. We will establish whether the number of FoxL2-expressing pre-granulosa cells formed in the ovary limits the number of follicles that can be formed, and determine whether activin increases follicle number by altering the size of the pre-granulosa cell pool. To gain insight into the biochemical processes they regulate in pre-granulosa cells, we will identify the genes that ActA and FoxL2 jointly-control, and investigate whether loss of either factor prevents these genes from being switched on or off correctly. Finally, we will investigate why primordial follicles fail to form correctly in FoxL2-deficient mouse ovaries, determine whether aberrant signalling by activin (or other signals) is the cause of this defect, and establish whether this can be corrected by restoring normal levels of signalling between cells. These studies will shed new light on how the number of follicles (and thus female reproductive lifespan) is established, provide insight into how mutations in FOXL2 in humans lead to infertility, and inform future studies to develop of new strategies to manage fertility.