The Scientist

Researchers have provided the first direct evidence that an evolutionarily conserved, retrotransposon-derived gene is essential for embryonic development, at least in mice, according to a study published in Nature Genetics this week. The findings suggest that the mammal-specific gene, Peg10, could have transformed egg-laying mammals into placental mammals more than 92 million years ago.

This gene family originated before the emergence of placental mammals, agreed Jean-Nicolas Vollf, at the University of Würzburg in Germany, who did not participate in the study. "There is one example of the genes being present in marsupials," he said, meaning that the domestication of the retrotransposon -- which led to the formation of the Peg10 gene family -- occurred before the formation of placental mammals.

The Japanese team, led by Tomoko Kaneko-Ishino from Tokai University in Japan, studied Peg10 knockout mice made by recombinant and cloning techniques, and found that no embryos survived beyond 10.5 days after conception. The researchers ascribed early embryonic lethality to defects in the placenta.

Peg10 is derived from a gene encoding a structural protein in a transposable element, the original function of which was to bind to nucleic acids, said Volff. A zinc finger domain is conserved in at least three genes in the Peg10 gene family – in dog, mouse, and human – suggesting that at least one of these conserved domains has to be still functional in binding to nucleic acids. "So probably it's a transcription factor," Volff said.

In an Email to The Scientist, Kaneko-Ishino agreed that the protein likely is a transcription factor. For instance, Peg10 bears a strong resemblance to another gene showing DNA binding activity in the promoter domain of the myelin basic protein gene, he said.

Genes derived from retrotransposons could also explain the origin of epigenetic imprinting, said Volff. Cytosine methylation was originally involved in host defence against transposable elements. "That's something which is a pretty old process," he said. Since methylation is also involved in imprinting and in the inactivation of the X chromosome, this means that there are at least some common mechanisms in both processes, according to Volff. Kaneko-Ishino said his group has hypothesized that retrotransposon insertion caused the establishment of some novel imprinted regions during evolution.

The role of the gene in early placenta development is probably not the only function of the gene, however, according to Volff. "This gene is expressed in a lot of tissues and organs during embryogenesis, and in a lot of tissues and organs in adults," he said.

While he agreed that the function of Peg10 is not exclusive to placental development, Azim Surani at the University of Cambridge, UK, who did not take part in the research, said the evidence still pointed to a primary role for Peg10 in that area.

In experiments using tetraploid rescue – which involves growing embryos that have a normal placenta despite missing a developmentally important gene – the team did get some animals to go on to develop to term, he said. If a particular gene is required in other aspects of embryonic development as well as placental development, this could not happen, Surani noted.

"If [the team] looked at an earlier stage of placental development, and compared normal versus mutant [expression] in placental tissue using microarrays or something like that," Surani said, they could derive further information on the gene's function. "It would be interesting to know what the targets for this gene are," he added.