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You’d think that in adult mammals ovaries are ovaries, and that’s it. They’re committed to being what they are.

ResearchBlogging.org

Or as geneticists would say, they’re terminally differentiated: they’ve reached the end of their differentiation pathway.

Well, it seems you’d think wrong. (This writer, too!)

In a stunning paper Henriette Uhlenhaut and 14 others show that if adult mice lose a Foxl2 gene, ovaries become testes.

These researchers raised mice in which they could delete the Foxl2 gene by treatment of tamoxifen, a compound that competes to block the estrogen receptor. (They used an inducible cre-recombinase system that responds to estrogen antagonist, tamoxifen. I’m summarising very lightly here for a general reader; biologists should start with the summary article.)

The surprising and unexpected result was that when adult mice were induced to lose their Foxl2 gene, their ovaries changed into testes! (I emphasis ‘adult’, as while embryos are still developing, adults are not.)

One up-shot is that this tells us that the ovary ’fights’ to maintain it’s status as an ovary throughout life. It’s not permanently committed. It is not a pathway that comes on ’by default’, either. Lose the Foxl2 gene and it changes.

Slightly more formally, this research shows that the ovary has to maintain constant suppression of the key testis development gene Sox9 by Foxl2; if not ovarian granulosa and theca cells change to become testicular Sertoli and Leydig cells, respectively.

Uhlenhaut and colleagues observe that the full set of genes associated with testis development becomes active and these XX (genetically female) mice produce similar amounts of the male sex hormone testosterone as XY (genetically male) mice.

My initial thoughts were that this work might be related to the well-known sex-reversal seen in some species of fish. The Australian scientists writing the summary article share this view (but coming from much more knowledge of the background than I have). They say it may also explain the female to male sex reversal of goats in polled intersex syndrome, where a region of their genome containing the Foxl2 gene has been lost. These workers also point to their own work, where ’knockdown’ of another gene, Dmrt1, required for testis development in chickens (and probably all other birds), results in feminization of the birds.

Taken together, it seems the view of the permanence of the status of the ovary in adult females in many species, not just mice, is under review.

It’s possible that this gene control pathway is also involved in human patients with premature ovarian failure or other disorders of sex development. I’m sure that these patients and their families will follow this emerging story closely.


Added after the article was written:

I’ve just realised that there is a video available explaining this work. I’m not sure if there is a way to “embed” this video, and I’m too short on time to experiment, so in the meantime at least you’ll have to visit there yourself.

It’s short (4 minutes, 18 seconds) and worth viewing, although you may want to replay it a couple of times if the terminology is a bit much for you.

It’s good to see Cell (the journal that published this work) making moves in this direction.

Update (23rd July 2011)

Ed Yong has written an account of a recent addition to this line of research, which shows the opposite situation to the masculinisation of ovaries described above – feminisation of testis cells through loss of the gene that represses feminisation of germ cells. This new work has parallels with the work I mentioned briefly that knockdown of Dmrt1 results in feminisation of chickens – it also acts through loss of Dmrt1. (I may attempt to write my own account of this work later, but I’m in two minds about trying to given Ed has already written on it. [He has the advantage of having access the journal embargoes so he can get these out on the day, before bloggers like me.])


References (both require a subscription, or a trip to a university library, sorry)

Summary article

Sinclair and Smith

Females Battle to Suppress Their Inner Male

Cell 139(6)1051 (2009)

doi:10.1016/j.cell.2009.11.036

Full paper

Uhlenhaut et al.

Somatic Sex Reprogramming of Adult Ovaries to Testes by FOXL2 Ablation

Cell 139(6) (2009)

doi:10.1016/j.cell.2009.11.021

Uhlenhaut NH, Jakob S, Anlag K, Eisenberger T, Sekido R, Kress J, Treier AC, Klugmann C, Klasen C, Holter NI, Riethmacher D, Schütz G, Cooney AJ, Lovell-Badge R, & Treier M (2009). Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell, 139 (6), 1130-42 PMID: 20005806

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