Tuesday, December 15, 2009

how to keep Ovaries Female? Ask "FOXL2".

The celebrated Male-ness transcription factor SRY, encoded by the Y-chromosome is needed for the differentiation of the indifferent gonads into Testis.
In this study, Mathias Trier, from EMBL demonstrates that in the mouse, a single factor, the forkhead transcriptional regulator, FOXL2, is required to prevent transdifferentiation of an ovary to a testis in the adult animal.
In one of their earlier studies in 2004, when they knocked out the gene in mice, females began to form ovaries, but later in development, the ovaries degenerated.

In the The current study the investigators let the mice develop ovaries normally, and then knocked down the gene once the animals reached adulthood.

Rationale behind the attempt:

1. Foxl2 is known to behave differently during development and adulthood. It regulates other genes important to organ differentiation.

2. During development, another gene, Wnt4, is expressed which is thought to be the major signal that suppresses the male program of development. After the female gonads develop, Wnt4 shuts off.
Contrarily, Foxl2's expression throughout the life of a female suggests that it is continually needed in female

Critical Observations:

Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific
genes including the critical SRY target gene Sox9.

Granulosa and Theca cells got reprogrammed into Sertoli- and Leydig- cell lineages

Testosterone levels were comparable to those of normal XY male littermates.

Change from ovarian cells to testicular cells didn't affect the outward physical appearance of the mice, i.e. the secondary sexual characters didnt undergo a change.

The overarching take-home-message from the work is that a fully differentiated adult organ has the potential - under conducive circumstances - to undergo radical remodeling, and undergo trans-differentiation.
And, FOXL2 and SOX9, which are gatekeepers of male- and female-ness oppose each other’s action
to ensure together the establishment and maintenance of the different female and male supporting cell types respectively.

But really, how do efficient epigenetic-changes happen in the cell in a span less than 48 hours, is a question not answered in this study.

Some questions which remain:

* Would the same phenomenon be possible in the Male as well? That is, the testis changing into an ovary.

* Female being the pre-differentiation default-sex , it is surprising that one' would need a factor to maintain "female-ness" throughout life?

* Moreover does SRY or its target genes, maintain "male-ness" in the adult male?

* And what is the role of FOXL2 in the Male?

* To change the epigenetics, phenotype, function and overall the total "identity" of a cell to another, by just 1   factor is a bit of a concern.
The most pertinent question, therefore perhaps is the following: Why  did mother-nature evolve such a "dangerous" strategy, whereby tinkering with just 1 gene, changes everything? To put it this way, what is the relevance of having a "master-player" and make a system increasingly vulnerable?


Somatic Sex Reprogramming of Adult Ovaries to Testes by FOXL2 Ablation.
Cell 139, 1130–1142, December 11, 2009
N. Henriette Uhlenhaut, Susanne Jakob, Katrin Anlag, Tobias Eisenberger, Ryohei Sekido, Jana Kress, Anna-Corina Treier, Claudia Klugmann, Christian Klasen, Nadine I. Holter, Dieter Riethmacher, Gu¨ nther Schu¨ tz, Austin J. Cooney, Robin Lovell-Badge, and Mathias Treier1


The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance.
Development, 131, 933-942 (2004)
Dirk Schmidt, Catherine E. Ovitt, Katrin Anlag, Sandra Fehsenfeld, Lars Gredsted, Anna-Corina Treier and Mathias Treier.