The human genome is comprised of 22 pairs of chromosomes, as well as two chromosomes that determine a person's gender. And researchers have known for decades that Down syndrome is associated with an extra copy of all or part of one of these: chromosome 21.
However, scientists have yet to identify the particular genes on this extra chromosome that cause the mental and physical abnormalities associated with the disorder. And this lack of knowledge has stymied drug development because drugs need targets, either the genes or the proteins they produce.
Now, however, in a recent issue of Proceedings of the National Academy of Science, researchers at UC San Francisco report that they have developed a mouse model that should enable them for the first time to delineate the role of specific genes in particular aspects of a Down syndrome-like disorder in mice. This model, says senior author Ting-Ting Huang, PhD, an assistant adjunct professor of pediatrics in the pediatric-medical genetics laboratory of Charles Epstein, MD, at UCSF should allow researchers to assess potential pharmacological agents and various forms of environmental enrichment, such as training, in these mice.
Ultimately, of course, the researchers hope such research would lead to the development of drugs to treat humans with Down syndrome, which causes mental retardation, major and minor physical abnormalities, often including heart disorders, and, in later life, Alzheimer's disease.
The new mouse model, called Ts1Cje, includes a partial third segment of mouse chromosome 16, the equivalent of a region on chromosome 21 in humans that is associated with Down syndrome.
It is not the first mouse model of Down syndrome--in fact, one of the previous standard models, known as "full trisomy 16," was also developed at UCSF--but it is the first to represent just a particularly small portion of the region of chromosome 16 that has strong parallels to some of the neurological disorders of the disease in humans. And this, said Huang, should make it easier to zero in on the role of individual genes.
Another previous standard model, Ts65Dn, includes a slightly larger third segment of chromosome 16 and causes more widespread learning and behavioral impairments than the newer model.
The researchers plan to tease out the specific role of genes in the newer model by using the older model as a backdrop.
"By analyzing this mouse model side-by-side with Ts65Dn," said Huang, "we can see what kind of physiological and biochemical differences there are between the two, and this may enable us to identify the role of some of the specific genes involved. Ultimately, we may be able to make corrections in these animals." The new mouse model includes approximately 20 genes that have been identified on the extra segment of chromosome 16 in the previous models.
The researchers say it is too early to draw strict parallels between the cognitive deficits in humans with Down syndrome and the learning, behavioral and structural abnormalities observed in the genetically engineered mice. However, they said, their new mouse model should yield insights into the chromosomal regions and the genes they contain that have the capability of disturbing neuronal structure and function when present in an extra copy. And the mechanisms by which these perturbations occur, they said, are likely to be relevant to the human situation.
In addition, they said, these animals can be used to assess potential pharmacological agents and various forms of environmental enrichment for their ability to improve learning and behavior. Already, the researchers have been able to improve the spatial learning deficits in the mice with training. In mice in the older, Ts65Dn model, the researchers succeeded in reversing neurodegeneration of one form of neuron with the use of nerve growth factor. "We have a ways to go," said Epstein, a professor of pediatrics and a senior author of the study, "but we're moving in on the genes that cause Down syndrome."