MRC National Institute for Medical Research, London
Science for Health
Turning an ovary into a testis
11 December 2009
The decision as to whether a developing embryo will become a male or a female is taken at an early stage during the formation of the gonads. In an XY embryo, the Y chromosome gene Sry triggers the formation of testes. Substances made by the testes, particularly the hormone testosterone, then cause the development of male characteristics throughout the rest of the embryo. In an XX embryo Sry is not present, so ovaries will develop instead of testes, and female characteristics will develop because the male-promoting substances are absent. However, Sry is only active for a brief period in the early embryonic gonads, and it works by activating a gene that is neither on the X or Y chromosome but on one of the other pairs of chromosomes common to males and females. This gene, termed Sox9, functions to promote and then maintain the formation of Sertoli cells in the testes, cells that support and nourish developing sperm. Sox9 is active in Sertoli cells throughout life. If Sry is absent and Sox9 fails to be activated, then cells of the same original type become follicle cells, which serve to support growing eggs (oocytes) in the ovary. Because Sry, Sox9 and testosterone are all male-promoting, so that in their absence female characteristics will develop, it had been considered that female development happens by default.
Robin Lovell-Badge (pictured) from NIMR's Division of Stem Cell Biology and Developmental Genetics, in collaboration with Matthias Treier and colleagues at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have shown that the activity of a single gene, Foxl2, is all that is required to prevent cells typical of an adult ovary from turning into those present in testes. When the gene is deleted from adult female mice, the cells rapidly change and begin to make male-specific factors including the male hormone testosterone. Moreover, these cells organize themselves into structures resembling sperm producing tubules – although these tubules are empty because the eggs cannot change to become sperm. This work shows very clearly that the male pathway needs to be actively suppressed in the adult.
The research teams at EMBL and NIMR looked further at the underlying molecular mechanism of this “gonadal sex reversal”. It was found that Foxl2 acts to suppress a particular DNA element (called TESCO) that the Lovell-Badge lab had previously shown was important to regulate the activity of the Sertoli cell-promoting gene Sox9. During the formation of ovaries in the embryo, there is evidence that several different factors serve to keep Sox9 off – presumably as a defence against having gonads that are a mix of ovary and testis, and consequent problems of intersex (or hermaphrodite) development. However, the work shows that in the adult Foxl2 is the only gene that retains this role. It is aided in this by estrogen receptors, proteins that respond to the female hormone estrogen. Therefore, when Foxl2 was deleted from adult ovaries, the Sox9 gene rapidly turned on and, recalling its role in normal testis development, lead to follicle cells becoming Sertoli cells and to the appearance of other testis cell types, including those that make testosterone (Leydig cells).
The research challenges several long held assumptions, such that female development happens by default, or that once formed, mature tissues are immutable or fixed. It also suggests ways of treating certain disorders affecting fertility or sexual development.
We were surprised by the results. We expected the mice to stop producing oocytes, but what happened was much more dramatic: somatic cells which support the developing egg took on the characteristics of the cells which usually support developing sperm, and the gender-specific hormone-producing cells also switched from a female to a male cell type.
Matthias Treier
Postnatal gonadal sex reversal in XX Foxl2 conditional mutant mice
PAS staining showing morphology of XX Foxl2f/f (control) and XX R26CreERT2;Foxl2f/f mutant gonads three weeks after TM administration. Left panel: wild-type, right panel: mutant at different magnifications.
The work provides insight into the evolution of mechanisms important for determining sex, because this competition between the male-promoting gene Sox9 and the female promoting gene Foxl2, is likely to operate in other animals, including species of fish that are known to change their sex according to environmental influences. Perhaps it means we are more like these fish than we thought!
Robin Lovell-Badge
These findings will have wide-ranging implications for reproductive medicine. For example, they may help to understand and treat some of the masculinising effects of menopause seen in some women, and some cases of premature ovarian failure where women lose all their oocytes early. It also offers for the first time the suggestion, although one that is still very speculative, that it might eventually be feasible to help treat some disorders of sex differentiation in children, for example, when XY individuals develop ovaries or perhaps when XX individuals develop testes or in intersex conditions. In some such cases it may be possible to retain fertility, which is otherwise inevitably compromised. Similarly, if it is possible to change adult gonad type from ovary to testes or even the reverse, it may eventually allow individuals with gender dysphoria, who feel they are trapped in the wrong sex, to change their gonads appropriately rather than having them removed surgically as part of their treatment to undergo gender reassignment. In such cases, however, while the new gonads might make the right hormones for their new sex, these individuals will lose their fertility.
Original article
The research findings are published in full in:
N. Henriette Uhlenhaut, Susanne Jakob, Katrin Anlag, Tobias Eisenberger, Ryohei Sekido, Claudia Klugmann, Anna-Corina Treier, Jana Kress, Dieter Riethmacher, Günther Schütz, Austin J. Cooney, Robin Lovell-Badge and Mathias Treier (2009)
Somatic reprogramming of an adult ovary to a testis
Cell, 139(6): 1130-1142. Publisher abstract.
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