BioWorld International Correspondent
LONDON - A mouse with cells containing almost an entire copy of human chromosome 21 is set to help researchers find out which genes are responsible for the features of human Down syndrome.
People with Down syndrome have an extra copy of chromosome 21. The Down syndrome model mouse - called Tc1 - also has three copies of all the genes on human chromosome 21, although two of the three are murine equivalents.
Scientists have tried to make mouse models of Down syndrome before, with varying degrees of success. Unlike all previous models, however, the new mouse has heart defects that resemble those seen in humans with Down syndrome. It also has memory and brain abnormalities.
Victor Tybulewicz, head of the division of immune cell biology at the National Institute for Medical Research in London, told BioWorld International: "We think this is probably the best mouse model for Down syndrome so far. It has got twice as many genes from human chromosome 21 as the previous best attempt, and it seems to model several of the features of human Down syndrome."
Importantly, he added, the availability of the Tc1 mouse will stimulate an "obvious" research program for his team and others to follow, to determine which genes - when present in triplicate - cause the characteristic features of Down syndrome.
Identifying which gene or genes cause the heart defects, or the specific type of leukemia to which those with Down syndrome are prone, could lead to therapies to prevent or treat those conditions. Tybulewicz said: "It might be possible to develop a drug that would knock down the activity of the gene or genes concerned."
The same technology used to develop the Down syndrome mouse also could be employed to make mouse models of other human chromosomal disorders, such as Edward's syndrome, where each cell has three copies of chromosome 18.
The work is reported in the Sept. 23, 2005, issue of Science in a paper titled: "An Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes."
Previous attempts to develop a mouse model for Down syndrome have faced a problem: The 250 genes that lie on human chromosome 21 are, in the mouse, distributed between chromosomes 10, 16 and 17.
The team, led by Elizabeth Fisher, of the Institute of Neurology at University College London, and Tybulewicz, decided that the simplest approach would be to add an entire copy of human chromosome 21. Their first step was to tag chromosome 21 in a human cell line with a drug-resistance gene that would allow them to select subsequently for cells containing that chromosome. They then treated the cells so that the chromosomes condensed into tiny pellets and could be centrifuged out. Those pellets were encouraged to fuse with mouse embryonic stem cells.
Having selected for those cells that had taken up chromosome 21, the researchers then injected them into early mouse embryos, which they then returned to the uteri of foster mothers. Animals in the resulting litters were chimeric. Breeding those mice gave rise to some animals that had the extra chromosome in their germ cells and thus were able to pass it on to the next generation.
The inserted chromosome contains 92 percent of all the genes known to be on chromosome 21. Tests showed that the chromosome was present in all tissues of the animals, and that many of the genes are "on," Tybulewicz said.
Further investigations showed that the Tc1 mouse has impaired memory, alterations in brain function, unusual skull morphology and heart defects, which appear to parallel the features of Down syndrome.
The stage now is set for researchers to breed the Tc1 mouse with knockout mice lacking one or more of the genes that are on chromosome 21. "We could take away 50 genes at a time," Tybulewicz said, "in order to track down whether the gene responsible for the heart defect is among them."
People with Down syndrome have a high risk of developing Alzheimer's disease, but the scientific community is going to have to wait a while to find out if the Tc1 mouse also models Alzheimer's.
The mice, which now have reached 20 months of age, do not develop the plaques in the brain that typify human Alzheimer's. "At this point there is no obvious pathology in the brain. Researchers who specialize in Alzheimer's say there are lots of other indicators to investigate, but this is going to take some time," Tybulewicz said.