Because the pool of ovarian follicles is set up during fetal life, the development of the ovary pre-determines female reproductive lifespan, including the time of onset of menopause. About 1-3% of all women undergo early menopause, either never going through menarche or stopping menstruation by the mid-30s, rather than reaching the standard reproductive lifespan of about 50. A fraction of such instances of early-onset premature ovarian failure (POF) is genetic. We have generated a mouse knock-out model for a gene that encodes a transcription factor, Foxl2, which that is mutated in some patients with early menopause (premature ovarian failure). We found that the earliest morphological anomalies involve a block in the formation of ovarian follicles, the fundamental units of ovary function. We then found that Foxl2-/- newborn follicle cells undergo female-to-male sex reversal, suggesting that dysregulation of sex determining genes even beyond the time at which they are usually thought to be active -- may be involved in ovarian failure in young and adult females. ? We moved on to provide evidence for a link between embryonic sex determining genes and premature ovarian failure. A notable example is seen in mice that we prepared lacking both Folx2 and Wnt4 (a double knock-out). In those mice, all cell types, including germ cells, reverse their sex during early development. This is the first experimental model of complete female-to-male sex reversal in mammals. We plan to continues to study the interaction of Foxl2 and male sex determining factors in the ovary, and have now identified arms of the pathways regulated by Foxl2 and Wnt4. Genes in those pathways will now be assessed for their role in vitro (organ cultures) and in vivo. In parallel, we are studying another transcription factor, Foxo3 that is also critically involved in the regulation of follicle dynamics and in premature ovarian failure in a mouse model. Toward this aim, we have generated transgenic mice over expressing Foxl2 and Foxo3 to test their effect on follicle fate and reproductive lifespan. ? Overall, we propose a paradigm in which Foxl2 is required both for ovary differentiation and for the maintenance of female sex determination in the ovarian soma; and we also suggest that defects in Foxl2 and its pathway may thus be involved in a number of types of fertility problems.
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| Ottolenghi, Chris; Pelosi, Emanuele; Tran, Joseph et al. (2007) Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Hum Mol Genet 16:2795-804 |
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| Ottolenghi, Chris; Uda, Manuela; Crisponi, Laura et al. (2007) Determination and stability of sex. Bioessays 29:15-25 |
| Ottolenghi, Chris; Omari, Shakib; Garcia-Ortiz, J Elias et al. (2005) Foxl2 is required for commitment to ovary differentiation. Hum Mol Genet 14:2053-62 |
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