They identify molecules necessary for sex determination in mammals

Most studies in the field of sex determination in mammals have focused, until now, on the so-called traditional genes, whose information is translated into proteins. However, recent research has revealed a new genetic component in this process.

This study is a collaborative work between research groups from the University of Granada (UGR) as well as the Andalusian Center for Developmental Biology (CABD), a joint center of the Higher Council for Scientific Research (CSIC), the Junta de Andalucía and the University Pablo de Olavide (UPO).

The new genetic component discovered is a group of small RNA molecules (microRNAs). The results of the study may provide clues about alterations in the sexual development and fertility of mammals.

The study shows that those small RNA molecules that are not translated into proteins, known as microRNAs, control sex determination in mammals. The embryonic gonad of mammals is a bipotential organ that can develop as an ovary or a testis. In XY individuals (in humans, men have XY chromosomes and women have XX), expression of the testis-determining gene (SRY) activates the testicular genetic program, while in its absence the ovarian program is activated. “In this work we have discovered that in mutant XY mice in which the miR-17~92 microRNA cluster is deleted, the SRY gene showed delayed expression compared to control males. As a consequence of this delay, XY mutant gonads experience a state of transient sexual ambiguity, initiating the ovarian and testicular program simultaneously. This effect, which had never been described before, resolves towards the activation of the ovarian program as development progresses,” explains Alicia Hurtado, CSIC researcher at the CABD who leads the work.

This study, therefore, demonstrates for the first time that microRNAs play a crucial role in the sex determination process. “In this way, the miR-17~92 cluster regulates the normal growth of the gonads and ensures that the expression of the SRY gene occurs at the precise moment of gonadal development, thus guaranteeing correct testicular differentiation,” says Darío Lupiáñez, scientist. who leads the CABD research group participating in the study. For the scientific community, it has been surprising that small non-coding RNA molecules can regulate a process so essential for the survival of mammalian species, such as sexual determination.

“The discovery of the SRY gene in 1990 marked the beginning of a great scientific effort to understand this process at the genetic and molecular level. Despite this, to date, only a few genes with an essential role in it have been identified. Therefore, the relevance of our study not only lies in having been able to add a new piece to the complex puzzle of the genetic control of sexual determination, but in the fact that this piece is a small group of microRNAs,” they indicate. Rafael Jiménez and Francisco J. Barrionuevo, who are at the head of the research group at the University of Granada (UGR).

The molecules identified in the new study are involved in sex determination in mammals. (Art illustration: Amazings / NCYT)

According to the scientists, this study opens new avenues to understand how microRNAs and other non-coding regulatory elements control the expression of coding genes involved in sexual differentiation. And although the work is applicable to mammals, it can probably also be transferred to other groups of animal species, since many of these microRNAs are evolutionarily conserved.

An aspect of potential relevance, in relation to this finding, is research into a type of conditions called “Differences in Sexual Development” (DSD). These types of conditions, which usually affect fertility in humans, can arise from genomic variations in factors that determine sex, such as microRNAs. Furthermore, alterations in sexual development can also occur in other mammal species, including domestic animals or livestock, and birds, which represents an economic problem in food production. Therefore, this new finding opens new perspectives for research in these contexts.

The study is titled “Complete male-to-female sex reversal in XY mice lacking the miR-17~92 cluster.” And it has been published in the academic journal Nature Communications. (Source: CSIC)