Revealing a rare example of adult cells reprogramming in vivo, researchers recently reported that deleting a single gene in an adult mouse's ovaries can transform ovary cells into cells resembling those found in testes. Some of these reprogrammed cells even start producing testosterone at levels found in similar cells in adult males.

Mathias Treier of the European Molecular Biology Laboratory (Heidelberg, Germany) and colleagues already knew that Foxl2 (the gene that they deleted) is needed for proper ovary functioning. In previous experiments, the apparently normal ovaries of female mice lacking Foxl2 started to deteriorate once the mice were born, but the precise function of Foxl2 remained unknown. To further study the gene, the research team genetically engineered mice so that they could turn off Foxl2 in adult ovaries of the mice (Cell 139, 1130–1142; 2009).

Credit: David Marchal

When the mice were 8 weeks old, the research team ablated Foxl2 by treating the mice with tamoxifen for 5 days. Three weeks later, Treier and his colleagues examined the treated mice and found that the granulosa cells of the ovaries had turned into cells that resembled the Sertoli cells typically found in testes. These Sertoli-like cells had even rearranged into structures resembling seminiferous tubules, which are characteristic of testes. Sperm-forming cells, however, were not present.

The researchers also analyzed the gonadal expression of Foxl2 and a gene called Sox9 that promotes formation of testes. They detected FOXL2 for only 2 days after the start of tamoxifen treatment, while SOX9 first appeared 4 days after treatment began. This suggests that Foxl2 and Sox9 cannot be highly expressed at the same time. One week after the start of treatment, SOX9 was expressed in all cells in a typical granulosa section, but by this time many cells had already begun differentiating into the Sertoli-like cells. This suggests that following loss of Foxl2, granulosa cells may begin to reprogram into Sertoli-like cells.

Further in vivo analysis by Treier's team showed that FOXL2 and the estrogen receptor ESR1 cooperate to repress Sox9. To maintain female gonad characteristics throughout adulthood, FOXL2 (working with estrogen receptors) must repress the expression of Sox9. Researchers think that by studying these opposing pathways, they might be able to better understand conditions such as early ovarian failure in females and sex differentiation disorders in children.