Ovary development gene identified in mice

A new driver of ovarian development, contributing to sex-specific organ differences, has been identified.

Usually, a mouse or human fetus with XY chromosomes will develop testes, and a fetus with XX chromosomes will develop ovaries. The Y chromosome gene Sry is necessary to develop testes, and if Sry is absent or unexpressed, the fetal gonads will develop into ovaries, even if a Y chromosome is present. However, drivers of ovarian development remained elusive, until a recent publication in Science, which describes the role of a gene called Wt1, now shown to be essential to gonad formation.

'When Sry, the testis determining gene, was identified in the early nineties, it was hoped that the other main players involved in the choice of making testes or ovaries would rapidly emerge. But although many other genes required have gradually fallen into place, it has taken until now, with a collaborative effort involving five European teams, to find an equivalent master ovarian determinant,' said senior author Dr Marie-Christine Chaboissier, from the Cote d’Azur University in France.

'It is perhaps a little ironic that this long-sought factor is a variant of the Wt1 gene which was also described at the same time, however, with the complexity of the gene and the system, we needed the modern tools of molecular genetics to obtain the proof' she added.

The gene Wt1 can produce three different proteins, depending on how its messenger RNA is spliced. By producing mice with different levels of one of these proteins – called '-KTS' – the scientists were able to understand its role in development.

In mice with no -KTS, there was no gonad formation, regardless of sex chromosomes. In XY mice with increased production of -KTS, Sry was repressed, and ovaries developed.

Gonad development is known to result in sex-specific differences in the functionality of organs, in particular the liver and kidneys. The development of ovaries in mice overexpressing -KTS was similar to the human condition Frasier syndrome, which results in gonadal dysgenesis and kidney problems. The researchers hope it may also help in understanding other kidney conditions such as Wilms' tumour.

'We have known about Wt1 and its variants for a long time, but the true role of the -KTS version has been hiding in plain sight until now!' said co-author Professor Robin Lovell-Badge, group leader at the Francis Crick Institute in London, and chair of trustees at PET (the Progress Educational Trust - the charity that publishes BioNews). 'This discovery should help us understand the very early stages of gonad development when critical decisions that affect not only the fate of the gonad, but the sex of the rest of the body, take place in just a few cells.'