Researchers take significant step forward in genetic sex reprogramming research

An international team of researchers, led by the University of Granada (UGR), has taken a significant step forward on the research on 'genetic sex reprogramming', which is closer now, although it's still an utopia.

In a research carried out in mice, the researchers have discovered that two genes (Sox8 and Sox9) with very important functions during the testicles embryonic development are responsible for keeping the testicle in adult animals.

If those genes are removed, it causes the disappearance of the seminiferous tubule (where the spermatozoa are formed) and the change of certain from masculine (testicular cells) to feminine (ovarian cells), a fact that had been never seen before in adults and clear proof of genetic sex 'reprogramming'.

This research, coordinated by the Biomedical Research Center and the department of Genetics at the University of Granada, has been published in eLife magazine, and counts with the participation of the University of Freiburg (Germany), the University of California-San Diego (United States), the University of British Columbia (Canada) and the Max Planck Institute for Molecular Genetics (Germany).

As Francisco Barrionuevo, Miguel Burgos and Rafael Jiménez, UGR researchers, explain, "for many years, we thought that adult gonads (testicles and ovaries) were stable and unchanging organs, developed in a definitive way and incapable of modifying their structure".

However, in was proved in 2009 that a key gene called Foxl2 must remain permanently active in adult ovaries in order to prevent granulosa cells (ovary-specific cells) from acquiring the genetic characteristics of Sertoli cells (testicle-specific cells).

"Similarly, Dmrt1, a gene normally active in Sertoli cells, plays a similar role in infant testicles, preventing cell transformation in the opposite way. Therefore, a new biological concept has arisen: sex maintenance, a mechanism by which certain genes have the task of preventing gonad cells to experience a genetic sex 'reprogramming'. However, this mechanism remained unbeknown to us until now", UGR researchers say.

Male-to-female genetic reprogramming

For this work, the researchers have induced Sox9 gene inactivation in Sertoli cells of adult, already mutant for Sox8 gene, mice testicles, and they have studied the changes in these double-mutated testicles from that moment on.

The researchers observed that those Sertoli cells "undergo male-to-female genetic reprogramming and start to express numerous granulosa genes, including Foxl2, and afterwards they undergo a programmed suicide process called apoptosis and die".

The process ends with the complete degeneration of the seminiferous tubules (where Sertoli cells and germ cells are), which transform into hollow space. Only Leydig cells, which are outside the tubules and produce testosterone, survive.

"In conclusion, our research has proved that, besides its key role in testicular development, the Sox9 gene along with Sox8 and Dmrt1 genes, also controls adult testicle maintenance. If they are removed, the testicle disappears and starts presenting a genetic expression profile typical of an ovary, which is similar to say that it transforms into an organ genetically similar to an ovary".

Francisco Barrionuevo and Rafael Jiménez note that, although the research has been carried out in mice, "it's possible that the same occurs in humans, although it's too soon to state that we can change people's sex by silencing these genes, which is science fiction by now".

Nevertheless, future research will try to elucidate the functional relationship between Sox8/Sox9 and Dmrt1 in adult Sertoli cells, which will contribute to know the scientific base of the testicular function, thus allowing the development of therapies against masculine infertility and sex reversal.

Source:

University of Granada

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