Sexual reproduction is a landmark in evolution because of the numerous genetic variations that it provides with each offspring: the union of two sex cells (spermatozoa and eggs) generates a new organism with genetic information from both parents. Although sexual reproduction needs two individuals of a different gender, a research group recently succeeded in creating mice with two biological fathers. More specifically, they have managed to modify the chromosomic content of a male sex cell to convert it into a female sex cell, hence making possible bipaternal mice.

All animal cells contain one pair of sex chromosomes (X/X for females and X/Y for males) but sex cells are unique since they only carry a single sex chromosome. This means that the chromosomic combination of one egg (X) with one spermatozoon (either X or Y) will determine the gender of the progeny. Thus, genetic manipulation of chromosomes could enable two sex cells of the same gender generating a new offspring.

Following this hypothesis, the authors of this work used embryonic stem cells from male mice carrying both X and Y chromosomes to generate X/X cells in vitro, by deleting the Y chromosome (X/0) and replicating X (X/X) through compounds that promote chromosomal missegregation during cell division. These sex-converted X/X cells were then transformed into egg precursors and aggregated with female gonadal cells, enabling successful conversion into mature eggs inside these “artificial ovaries”. Finally, the converted eggs were exposed to mouse sperm, resulting in embryos that were implanted into females that eventually gave birth to pups with two fathers.

Another interesting aspect of this study are the results obtained with triploids cells regarding fertility. Triploidy happens when one set of paired chromosomes - different to the sex ones – has an extra chromosome, leading to disorders such as Down syndrome. The investigators obtained triploid cells from male stem cells and observed that when they were converted into diploid X/X cells they could differentiate into eggs, contrarily to triploid X/X cells, which failed in this conversion.

Altogether, the results provided in this study highlight the clinical potential of stem cells in reproductive biology by breaking two rules of sexual reproduction. Firstly, the generation of mice through the fusion of two sex cells, originally of the same gender.  Secondly, the possibility of original triploid cells of giving rise to a healthy offspring, which is an important step in reproductive research as triploid Down syndrome patients show infertility.

Original article

Murakami K, Hamazaki N, Hamada N, et al. Generation of functional oocytes from male mice in vitro. Nature. Mar 15 2023;doi:10.1038/s41586-023-05834-x