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Mice with Two Mothers
Gene “Imprints” Were Key to Making Fatherless Mice

By Nancy Touchette

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Kaguya, the offspring of two female mice, inside a piece of bamboo.
Researchers in Japan have shown for the first time that female mice can reproduce without help from the other half of the species. Although embryos from mice and other mammals have been created in the past without using any DNA from males, this was the first time an offspring was born.

The new research resulted in the birth of two female mice, produced by mixing two sets of female chromosomes. One of the mice lived to adulthood and mated with a male, producing offspring.

Many species of plants and animals can reproduce without sperm in a process known as parthenogenesis. But nature has decided that for mammals, sexual reproduction works best with contributions from both the male and female genomes. Indeed, researchers have long been puzzled by what prevents parthenogenesis in mammals.

The answer apparently lies in the way genomes are marked, or imprinted. A small number of genes are tagged so that only the maternal copy or the paternal copy of the gene is active.

In the new study, Tomohiro Kono of Tokyo University and his colleagues changed the way two of these genes were marked so that two sets of female genes, derived from eggs, could combine to form living embryos.

Although the research is unlikely to lead to new ways to make human babies in the near future, if ever, it does show how important imprinting is to the development of an embryo. And it may help researchers who are trying to use therapeutic cloning to produce embryonic stem cells. Researchers believe that these specially imprinted genes help regulate the activity of other genes throughout the genome.

“This study confirms what we have long suspected,” says Paul DeSousa of the Roslin Institute in Edinburgh, Scotland. “If we are ever going to make cloning more efficient, we are going to have to focus on these imprinting errors.”

De Sousa and his colleagues are trying to develop human stem cells from human embryos created through parthenogenesis. He says that the although the approach used by the Japanese researchers was useful in answering questions about the importance of imprinting certain genes, it is not a practical technique for creating cloned or parthenogenetic embryos from human cells.

In the new study, reported in Nature, researchers focused on two genes known to be important in imprinting. The Igf2 and H19 genes both reside on chromosome 7 in mice and are also imprinted in human embryos. As the mouse egg matures, it becomes specially tagged so that H19 is active and Igf2 is inactive.

But the same genes are oppositely marked in sperm. In male chromosomes, the H19 gene is inactive and the Igf2 gene is active. Normally, when two sets of maternal chromosomes are mixed, embryos fail to develop, because the genes are not activated appropriately.

Kono and his colleagues got around this by using mature mouse eggs that contained one set of chromosomes with normally imprinted female genes. The second set of chromosomes, which came from immature eggs, was not tagged, and the H19 gene had been deleted.

And although this set of chromosomes was from a female mouse, the Igf2 gene was active, as though it had come from a male genome.

The results suggest that proper imprinting of the H19 and Igf2 genes is important for normal development. The efficiency of the method of producing new offspring was very low, however. Of more than 500 embryos produced, only two survived to birth.

Creating the parthenogenetic embryos required a fair amount of genetic manipulation, and this probably contributed to the loss of embryos, says DeSousa.

“But they managed to get the imprinting to resemble the paternal genome closely enough to allow development to proceed,” he says. “This is a significant achievement.”

Kono, T. et al. Birth of parthenogenetic mice that can develop to adulthood. Nature 428, 860-864 (April 22, 2004).

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