(Feb. 8th, 2010) Researchers from the European Molecular Biology Laboratory (EMBL) in Heidelberg are challenging the dogma that in mammals developing female traits is the default pathway after fertilization. Rather, male development needs to be actively repressed.
Countless examples of gender inequality exist in nature. But what does it mean to be male or female and how distinct are the differences? Gender determination and its underlying mechanisms have fascinated scientists for years. Sex chromosomes were discovered and the mechanisms from fertilization to birth were characterised – however, as is typical in science, there is always more.
A collaboration between Mathias Treier’s group at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany and Robin Lovell-Badge’s group at the National Institute for Medical Research (MRC) in the UK, gave birth to a thought-provoking study in the December 2009 issue of Cell (Uhlenhaut et al., vol. 139, 1130-42), which challenges the established theory that developing female traits is the default pathway after fertilization. For us non-reproductive biologists, it also highlights the plasticity of the adult ovary and the possibility of altering gender in postnatal animals.
Remember basic course “Reproductive Biology”: females inherit an X chromosome from each parent, whereas males are heterogametic, receiving an X and Y chromosome from mother and father, respectively. Males become males because of the Sry gene located on the Y chromosome. SRY directly activates the autosomal Sox9 gene, which kick-starts the differentiation process transforming the bipotential gonad to the male gonad (testes). Without SRY or SOX9, the bipotential gonad becomes an ovary – hence female differentiation being the default. Interestingly, males with XX chromosomes exist where Sox9 was activated in the bipotential gonad. Mechanisms underlying these reversals are not fully understood but genes have been identified, which normally oppose the male pathway, including the focus of the Uhlenhaut paper, Foxl2.
Deleting Foxl2 in ovaries of adult female mice resulted in the appearance of structures resembling seminiferous tubules of the testes and cells similar to testicular Sertoli cells. Differentiation of the ovary’s granulosa and theca cells to Sertoli-like and Leydig-like cells increased testosterone levels, the principal male sex hormone, similar to those in XY pups. Furthermore, Sertoli and Leydig cell markers were upregulated together with other genes involved in testes determination, including Sox9.
Previous work by Lovell-Badge’s group identified TESCO, a DNA element which regulates Sox9 expression (Nature 453: 930-4). Therefore, the question of a link between FOXL2 and Sox9 arose. The presented evidence shows FOXL2 acting together with the oestrogen receptor to bind TESCO, thus inhibiting Sox9 activation. The data also suggests that Sox9 can be activated in adults.
With their new study, Treier and colleagues have now challenged the dogma that the female phenotype is the default state by showing that Sox9, which drives male development in utero, needs to be actively repressed (by FOXL2) in adult females to maintain the female phenotype. The authors go on to stress the potential medical benefits of their results in treating sex differentiation disorders in children and premature menopause in women.
Rosemarie Marchan