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STEM CELLS

Mice from same-sex parents produce their own offspring

mice

Published 22 October 2018

Generation of bimaternal and bipaternal mice overcomes reproductive barriers of genomic imprinting. Cristina Eguizabal and colleagues from the SIG Stem Cells report.

Researchers led by Professor Qi Zhou from the Chinese Academy of Sciences in Beijing have reported the generation of mice using DNA from two mothers and two fathers.(1) The bimaternal offspring were mostly normal and, in some cases, able to reach adulthood. Some bipaternal mice also developed to term, but showed severe growth defects and died shortly after birth. Nevertheless, bipaternal reproduction has not been previously achieved in mammals.

It has been well established that mammalian development requires complementary contribution from both sexes to progress successfully. Differences between the maternal and paternal genome, including sex-specific epigenetic modifications, are necessary to promote the favourable exchange of genetic information. This phenomenon, known as genomic imprinting, leads to monoallelic, parent-specific expression of certain genes in the embryo and is crucial for normal development following fertilisation. Imprinted epigenetic marks are erased in the germline during primordial germ cell differentiation and become independently established during oogenesis and spermatogenesis. As such, genomic imprinting represents the main barrier for uniparental reproduction.

In a tremendous effort to overcome this obstacle, Li et al used CRISPR/Cas9 to delete imprinted regions in parthenogenetic and androgenetic embryonic stem cells (ESCs) to generate bimaternal and bipaternal mice. Firstly, modified parthenogenetic haploid ESCs were injected into MII oocytes to generate bimaternal pups. Efficiency, however, was low, with 14% of the embryos developing to term and normal live birth. Remarkably, some of the bimateral mice were able to reach adulthood and have offspring of their own, some of which also developed normally.

To generate bipaternal mice, the researchers initially co-injected sperm and androgenetic haploid ESCs into enucleated oocytes. However, none of the embryos made it to term and were restricted to E8.5 after transfer. Finally, Li et al used tetraploid complementation by injecting modified androgenetic diploid ESCs into tetraploid embryos and were able to generate live full-term bipaternal pups, with a ~1.2% efficiency. The mice, however, showed severe developmental deficiencies and died within 48 hours. Nevertheless, this is the first study to overcome bipaternal reproduction barriers in mammals. Moreover, to generate the bipaternal pups, Li et al performed extensive genetic manipulations of seven imprinted regions in ESCs, a commendable technical feat in itself.

Overall, these findings are of exceptional value for understanding aspects of mammalian reproduction. However, applications in the human remain unfeasible. The low success rate and abnormal development observed demand further research into genomic imprinting and its regulatory processes. Imprinted genes influence a wide range of biological processes, which also extend into adulthood and may have profound roles in a variety of adult-onset diseases. Thus, ensuring the safety of genetic manipulations involving imprinted genes will be exceptionally challenging. At present, the risk of severe abnormalities remains too high. Future studies in animal models will certainly provide a greater understanding of the function, adaptability and evolution of imprinted genes, as well as their important roles in development and disease.

1. Li Z. Wang L-Y, Wang L-B, et al. Generation of bimaternal and bipaternal mice from hypomethylated haploid ESCs with imprinting region deletions. Cell Stem Cell 2018; 23: 1-12.