One Chromosome Too Many

A dash of humanity. A copy of human chromosome 21 (green) added to mouse ES cells has yielded mice with symptoms of Down syndrome.

After more than a decade of frustrated efforts, researchers have finally pulled off a genetic engineering first, creating a strain of mice with a nearly complete copy of human chromosome 21. The strain's unusual genome mimics the genetic makeup of people with Down syndrome, the most common inherited form of mental retardation.

People with Down syndrome have an extra copy of chromosome 21, resulting in mild to moderate mental retardation and abnormal facial features. Efforts to model Down syndrome in mice have been complicated by the fact that the mouse versions of the genes on human chromosome 21 are inconveniently scattered across three mouse chromosomes.

To create a better mouse model, researchers led by Elizabeth Fisher at the Institute of Neurology in London and Victor Tybulewicz at the National Institute for Medical Research, also in London, attempted something that had never been done before: They tried to put the entire human chromosome into mice. It wasn't easy. The team extracted chromosomes from human fibroblast cells and transferred them into mouse embryonic stem (ES) cells. A marker gene indicated which ES cells had picked up chromosome 21--usually just one or two cells out of a batch of tens of millions, Tybulewicz says. The researchers injected the ES cells into early mouse embryos, which were carried to term by a foster mom. Additional tinkering was needed to create a strain of mice that passed the extra chromosome on to their offspring.

That strain, called Tc1, has about 92% of human chromosome 21, the team reports in the 23 September issue of Science. It also has several characteristics of Down syndrome. Although there's no test for mental retardation in mice, the Tc1 mice have deficits of spatial learning and memory similar to those found in Down syndrome patients; they also have a deficit in "long-term potentiation," a neurophysiological process thought to underlie learning and memory. Perhaps most significant, the mice have heart defects like those seen in 40% of Down syndrome patients. "That's a first," says Stylianos Antonarakis, a geneticist at the University of Geneva in Switzerland. "No other mouse so far has the heart defect."

"This is going to have a huge impact on Down syndrome research," says Roger Reeves, a geneticist at Johns Hopkins University in Baltimore.

Related sites
A description of Fisher's research
Tybulewicz's site
Information about Down syndrome from the National Institute of Child Health and Human Development

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