News & Views Archives
Issue No. 2, Winter 2005
The launch of our new website a few months ago was quite successful. Many readers have contacted us with feedback and questions. Some have sent pictures of their children and shared their experience with Down syndrome from a parent’s perspective. Thanks to each of you for contributing your thoughts and ideas. Your input gives us a sense of what the Down syndrome community needs most, and how we can accommodate this on our website.
We have received phone calls and emails from parents specifically wanting to know more about the Down syndrome clinic. Due to a delay, the anticipated opening of the clinic will be postponed until later in the year. We apologize for this disappointment. Please keep revisiting our clinic web page for the latest developments.
Here is a success story we would like to share: Last summer a family from Texas approached our Center with their fundraising idea: to create a little stuffed mouse to represent the mouse models used in Down syndrome research. They decided to call their effort "Adopt-A-Mouse for Down Syndrome", and started selling the mice for the symbolic amount of $ 21. Half a year later, their campaign has made national news! "Adopt-A-Mouse" is now a fundraising program for the Down Syndrome Research and Treatment Foundation.
The Down syndrome mouse - A historical perspective & what the future may hold
By Sietske Heyn, Ph.D.
Why are we using mice to study Down syndrome? Why not dogs or kangaroos you may wonder. Mice have been a very useful research tool for many decades. There are several reasons for this. Although mice are not very close relatives to us humans, they nevertheless share a large number of similar genes. In addition, the reproductive cycle of mice is very short, they produce large litters, and they have a short life span (2-3 years). Mice are relatively cheap to breed and maintain (compared to larger mammals), and permit us to conduct experiments not possible in humans.
Down syndrome and other trisomy (Ts) mouse models have been available since the 1970ies (1,2). In the case of Down syndrome, these mice (called Ts16) have an extra copy of mouse chromosome 16, which contains more than 80% of the genes found on human chromosome 21 (3). There are several problems with these mice. First, they do not survive past birth, precluding studies of the development and function of the nervous system as well as ageing processes. Second, mouse chromosome 16 contains genes that are not found on human chromosome 21. The Ts16 mouse is thus not a good model for Down syndrome as it is not trisomic for all human chromosome 21 genes, and in addition, it is trisomic for genes not implicated in the disorder.
Several years ago, the first segmentally trisomic Down syndrome mouse model called Ts65Dn was engineered (See mouse pictures) (4). This mouse has an extra copy of a region of mouse chromosome 16 that is conserved in human chromosome 21, including genes from the Down syndrome critical region (DSCR). It is generally believed that this region contains many genes that when triplicated may cause much of what we know as Down syndrome. Ts65Dn mice survive to adulthood and express some characteristics of Down syndrome such as developmental delay, hyperactivity, weight problems (5), craniofacial dysmorphology (6), impaired learning, and behavior deficits (7). Currently, Ts65Dn is the most well studied Down syndrome mouse model.
While the Ts65Dn mouse has given and is still offering us much sought after insights into Down syndrome, other mouse models are needed. These include mice in which all human chromosome 21 genes are triplicated, as well as mice with only small triplicated gene segments. The former would constitute the most complete genetic model, recapitulating the majority if not all Down syndrome features. At present, a mouse with an entire set of triplicated human chromosome 21 genes has not been made, though several groups are working hard to make this mouse. This is quite challenging as it will require triplicating genes on mouse chromosomes 10, 16 and 17. Scientists have had more success with creating segmental chromosome 16 trisomies (See Figure 1). Like Ts65Dn mice, they have an extra copy of much smaller gene segments of chromosome 16 (8-10).
Why would we want to create mice that contain less triplicated genes, when after all, Down syndrome in most cases involves a third copy of the entire chromosome 21? The current trisomy 21 hypothesis states that characteristics of Down syndrome are triggered by a genetic imbalance or over-expression of one or more normal genes on the extra copy of chromosome 21. A major goal of Down syndrome research is to figure out how an imbalance of specific genes from human chromosome 21 may correlate with specific clinical aspects of the disorder. For example, researchers may want to find out which extra genes on chromosome 21 contribute to heart defects or leukemia.
Toward this goal, it is imperative to engineer mice that have very small triplicated gene segments. Ideally, one would like to go through one gene at a time so that we can tease out exactly which gene(s) are the most crucial in terms of their effect on Down syndrome. Logistically, this is almost impossible to do at the moment. The next best approach is to generate a collection of mice with varying lengths of triplicated chromosomal segments.
To date, the Garner and Huang laboratories at Stanford University are collaborating with Dr. Roger Reeves (Johns Hopkins University) to engineer a series of new mouse models with so called “tandem duplications.” Unlike current mouse models that are trisomic, these new mice will have a duplicated gene segment nested in one of their two normal chromosome 16 copies. Thus, these mice will have three copies of some genes, but still only two chromosomes rather than three (See Figure 2). Dr. Feng in the Garner lab is in the process of designing and engineering six new mouse models in which the nested gene segment along chromosome 16 will be consecutively 20 genes shorter.
Once this series of mice has been established, phenotypic differences between the models can be compared and traced back to the 20 genes by which the mice differ. One can then focus exclusively on the phenotypes related to the brain, thereby further narrowing down the genes of interest. Creating these mice is a painstakingly laborious and expensive task that requires many years of work. The generation of just one new mouse line will take one year before it can be used.
In addition to continuing our studies with Ts65Dn and the other currently available mouse models, we hope that this new generation of mice will give us even more insights into how the different triplicated genes contribute to Down syndrome. In the long run, we hope that the identification of specific genes will help us to rationally design therapies and treatments.
Gropp, A., Kolbus, U., and Giers, D. (1975) Systematic approach to the study of trisomy in the mouse. II. Cytogenet. Cell Genet. 14:42-62
Epstein, C.J., Cox, D.R., and Epstein, L.B. (1985) Mouse trisomy 16: An animal model of human trisomy 21 (Down syndrome). Ann. NY Acad. Sci. 450:157-168
Akeson, E.C., Lambert, J.P., Narayanswami, S., Gardiner, K., Bechtel, L.J., and Davisson, M.T. (2001) Ts65Dn – localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome. Cytogenet. Cell Genet. 93(3-4):270-276
Davisson, M.T., Schmidt, C., and Akeson, E.C. (1990) Segmental trisomy of murine chromosome 16: A new model system for studying Down syndrome. Prog. Clin. Biol. Res. 360:263-280
Davisson, M.T., Schmidt, C., Reeves, R.H., Irving, N.G., Akeson, E.C., Harris, B.S., and Bronson, R.T. (1993) Segmental trisomy as a mouse model for Down syndrome. Prog. Clin. Biol. Res. 384:117-133
Richtsmeier, J.T., Baxter, L.L., and Reeves, R.H. (2000) Parallels of craniofacial maldevelopment in Down syndrome and Ts65Dn mice. Dev. Dyn. 217:137-145
Reeves, R.H., Irving, N.G., Moran, T.H., Wohn, A., Kitt, C., Sisodia, S.S., Schmidt, C., Bronson, R.T., and Davisson, M.T. (1995) A mouse model for Down syndrome exhibits learning and behaviour deficits. Nature Genetics. 11:177-184
Sago, H., Carlson, E.J., Smith, D.J., Kilbridge, J., Rubin, E.M., Mobley, W.C., Epstein, C.J., and Huang, T. (1998) Ts1Cje, a particular trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc. Natl. Acad. Sci. 95:6256-6261
Olson, L.E., Roper, R.J., Baxter, L.L., Carlson, E.J., Epstein, C.J., and Reeves, R.H. (2004) Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes. Dev. Dynamics. 230:581-589
Sago, H., Carlson, E.J., Smith, D.J., Rubin, E.M., Crnic, L.S., Huang, T., and Epstein, C.J. (2000) Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Ped. Res. 48(5):606-613
Paper of interest
Drs. Patterson and Costa from the University of Denver and University of Colorado Health Sciences Center have written a very nice review entitled “History of genetic disease: Down syndrome and genetics - a case of linked histories.” It includes a great historic timeline describing the parallel discoveries in Down syndrome and genetics.
Abstract from the article
Down syndrome, the most common genetic cause of intellectual disabilities, was first described in 1866, during an era of great change in our understanding of genetics and evolution. Because of its importance, the history of research on Down syndrome parallels the history of human genetics. In many instances, research on Down syndrome has inspired progress in human genetics. In this article, we describe the interplay between advances in the understanding of genetics and the understanding of Down syndrome from its initial description to the present, and on the basis of this historical perspective, speculate briefly about the future of research on Down syndrome.
This article can be found in Nature Review Genetics, 2005, January 10, e-publication, ahead of print