This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a
It has been established that premature ovarian failure (POF), or the failure of the ovaries before age 40, can affect approximately 1% of women [3]. However, the cause of POF among women varies significantly. It has been estimated that up to 30% of women experiencing POF have a genetic cause, although not many gene targets have been directly correlated [4]. Since oocytes regularly undergo proliferation and apoptosis (programmed cell death) throughout the cell cycle, the smallest interruption in that process could cause a significant consequence.
Researchers set out to investigate the role intra-oocyte Foxo3a plays on the regulation of follicular activation and development. It has previously been identified that that follicle activation occurs when oocytes grow and the granulosa cells that surround them mature. This relationship between oocytes and granulosa cells plays a dominant role in follicular development. Granulosa cells have shown the ability to relate the growth of oocytes. Along with the aid of granulosa cells, oocytes are also capable of secreting other factors that play a role in follicular activation. One such factor that plays a direct role in follicular development is the Kit ligand that is produced by granulosa cells. Kit1 is capable of activating the oocyte phosphatidylinositol 3-kinase (PI3K) pathway. This pathway involves activation of a molecule Akt (protein kinase B) that is growth enhancing as well as the suppression of the Akt substrate Foxo3a. This molecule is a transcription factor that regulates cell-cycle and apoptosis. With this knowledge at hand along with knowing that mice without Foxo3a exhibit abundant activation of primordial follicles, investigators set out to identify the role of the PI3K pathway in oocytes [2].
Through the use of a transgenic mouse to keep the level of active Foxo3a expression in oocytes constant. This study showed that the expression of Foxo3a is significantly down-regulated in primary and more-developed follicles. It is also suggested that Foxo3a may contribute to the restraining of primordial follicle activation. The constant expression of Foxo3a leads to retardation of oocyte growth and follicular development. Not only is Foxo3a directly correlated to the retardation of oocyte growth, but that retardation is also a result of hindered oocyte-granulosa communication due to insufficient gap junctions. Along with these findings, it was also discovered that moderate and controlled activation of the PI3K pathway is also important in controlling oocyte growth and follicular development. All of this data enables great insight into a genetic factor of premature ovarian failure (POF).
References:
[1] Liu, L., Rajareddy, S., Reddy, P., Du, Chun., Jagarlamundi, K., Shen, Y., Gunnarsson, D., Selstam, G., Boman, K., Liu, K. (2007). Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a. Development 134, 199-209.
[2] Castrillon, D. H., Miao, L., Kollipara, R., Horner, J. W., DePinho, R.A. (2003). Suppression of ovarian follicle activation in mice by transcription factor Foxo3a. Science 301, 215-218.
[3] Coulam, C., Adamson, S., Annegers, J. (1986). Incidence of premature ovarian failure. Obstetrics and Gynecology 67, 604-606.
[4] Vegetti, W. (1998). Inheritance in idiopathic premature ovarian failure: analysis of 71 cases. Human Reproduction 13, 1796-1800.
