A new study published in Science by Humphrey Yao, Ph.D. challenges this age-old concept of the female pathway as “default” and shows that the development of femaleness is also an active process. The authors implicated a protein called COUP-TFII as a key player that is required to actively eliminate the wolffian duct in a developing female embryo in order to give it female characteristics.

Before we are born, a set of embryonic structures form the basis of our male or female reproductive organs. These embryonic structures are known as Wolffian and Müllerian ducts The researchers had originally set out to study how tissues on the outside of the early ducts communicate with the lining of the tubes in the early embryo to direct proper organ development. Since the COUP-TFII protein is produced in that outer layer, Yao suspected it could play an important role in this signaling process. His team mutated the gene for COUP-TFII in mice so that this protein was no longer produced by the developing embryos. They observed that in these mutant mice the communication in the reproductive tissue of early female mouse embryos was disrupted. However, what was surprising was that these female embryos retained not only the female müllerian duct but also the male wolffian duct.

It does seem that female is default is not true, and much more interesting that we commonly hear in textbooks.


Sex determination in mammals involves the development of a bipotential gonad into either a testis or ovary. Sertoli cell differentiation and thus testis formation is under the control of the regulatory gene Sry (Koopman et al. 1991). The Sry gene product was later shown to upregulate the expression of Sox9, which is key in testis development (Sekido and Lovell-Badge 2008). On the other hand, ovarian development is centered on β-catenin stabilisation by WNT4 signalling, which is thought to inhibit Sox9 expression (Bernard et al. 2012). Because Wnt4 is expressed basally in the genital ridge and testis development apparently depends on Sry expression, the ovarian pathway has often been described as default; in other words, the pathway that the gonad would take in the absence of Sry.

However, ovarian development is in fact an active process requiring the correct balance of many factors, including a transcription factor called forkhead box protein L2 (FOXL2) (Yao 2005). Studies in mice showed that Foxl2 is expressed in the ovary, both during development and in adulthood. Knockout of the gene prevented granulosa cell differentiation during development, leading to ovarian failure (Schmidt et al. 2004) and increased expression of markers for the testis development pathway (Ottolenghi et al. 2005). Furthermore, mutations of this gene are responsible for XX sex reversal in goats (polled intersex syndrome, PIS) (Pailhoux et al. 2001). Taken together, these experiments indicate that Foxl2 is required for ovarian development and that its absence can favour testis formation.