The origin of ovarian development finally discovered · Inserm, science for health

While the gene that triggers the development of testes in humans and mice has long been known, the gene responsible for the development of ovaries had not yet been discovered. An international collaboration involving researchers Inserthas just filled this gap.

In humans, as in mice, the sex of an individual is genetically determined by its sex chromosomes: one X chromosome and one Y (XY) lead to the development of testes, two Xs (XX) to that of ovaries. This process begins at the embryonic stage with progenitor cells that are identical for both sexes and differentiate into Sertoli cells to allow the development of testes in XY individuals or pregranulosa cells that lead to the formation of ovaries in XY individuals. XX. Once the gonads (testicles or ovaries) are formed, they influence the sexual development of the entire individual.

Ovaries by default?

The gene responsible for the differentiation of the gonadal precursors into Sertoli cells (i.e. the gene at the origin of the testes) has been known for about thirty years: it is the gene Excuse me, located on the Y chromosome. However, no gene that triggers ovarian development has yet been identified. So much so that scientists long thought it was a “standard” mechanism: it was imagined that there wasn’t one Excuse meCell differentiation was directed toward the formation of female rather than male gonads. And they actually inhibit the expression of in mice Excuse me induces the formation of ovaries in XY animals.

The work carried out by Élodie Grégoire in Marie-Christine Chaboissier’s team at the Valrose Institute of Biology in Nice, in collaboration with other laboratories in France, the United Kingdom, the Netherlands and Switzerland, shows that this is not the case: there actually is a gene responsible for the development of the ovaries.

WT1(-KTS), a key player

The starting point for this work was the genetic anomaly of Frasier syndrome, a disease that leads to the presence of female sexual organs, particularly in XY people. It is linked to a gene mutation Wt1 This allows the synthesis of two slightly different proteins: the WT1(+KTS) protein and the WT1(-KTS) protein, which differs from the first by the absence of three proteins amino acids (a lysine, whose symbol is the letter K, a threonine, symbolized by T and a serine S).

The mutation is present in Frasier syndrome Wt1 leads to overexpression of WT1(-KTS) and deficiency of WT1(+KTS). The researchers studied the development of mice that had this mutation and noted the appearance of ovaries in all of these animals. To find out whether this phenomenon was triggered by overexpression of WT1(-KTS), they developed another animal model in which it is possible to overexpress WT1(-KTS) while maintaining normal WT1(+KTS) levels. This experiment confirmed that overexpression of WT1(-KTS), regardless of the level of WT1(+KTS), triggers ovarian development regardless of whether the individual is XX or XY.

“ Our various experiments show that WT1(-KTS) is expressed in animals of both sexes. However, Excuse me works earlier, ensuring testicular development in XY individuals. If, on the other hand, the expression of Excuse me is impaired or delayed, or when WT1(-KTS) is prematurely overexpressed as in Frasier syndrome, differentiation into pregranulosa cells is accelerated and leads to the systematic formation of female genitalia », describes Élodie Grégoire.

This very fundamental work not only fills an old gap in our knowledge of sexual development, but will also lead to a better understanding of the signaling cascade that leads to ovary formation from the first triggering signal. “ Ultimately, physicians will likely be able to better characterize certain abnormalities in sexual organ development and provide more appropriate genetic counseling. », predicts the engineer.

Élodie Grégoire is an Inserm engineer on the team Genetics of sex determination and fertility