News & Views Archives

Issue No. 5, Fall 2005

We thank all the parents who sent us pictures of their children for our website! It makes our site much more personal.

Hopefully, a lot of you were able to participate in a local Buddy Walk this October in celebration of Down Syndrome Awareness Month.

More and more people are calling and emailing us with patient referral requests for our Down syndrome clinic. We regret that the clinic is not opening its doors as quickly as we had anticipated. The clinic is however, in the final planning stages. At this point, we would like to restate that we are not yet taking any patient referrals. Rest assured that we will make a big announcement once we have a specific opening date for the clinic.

In this issue of News & Views, we review a recent article, which reports on a new Down syndrome mouse model called Tc1. This new mouse model provides yet another useful research tool for understanding the mechanisms behind trisomy 21.

In the spotlight

Tc1 - A New Down Syndrome Mouse Model
By Sietske Heyn, Ph.D.

During the past few decades, mouse models have become very useful tools for scientists to study human disorders. Even though we humans do not resemble mice, we do share a lot of similar genes with these creatures. In addition, mice are relatively cheap, breed quickly and can be used to carry out experiments not possible in humans. Down syndrome is no exception: the first mouse model called Ts16 was created in the 1970ies (1,2) and several other models such as Ts65Dn and Ts1Cje now exist (for a review see News & Views issue 2).

The ideal Down syndrome mouse model is one in which all +/- 250 genes found on human chromosome 21 are triplicated. This is a challenging task because the genes found on human chromosome 21 are spread over three mouse chromosomes (chromosomes 10, 16 and 17). So to create a model that contains a complete set of genes equivalent to human chromosome 21, one has to create a chromosome that contains genes from mouse chromosomes 10, 16 and 17.

The first Down syndrome mouse model (Ts16) has an extra copy of mouse chromosome 16, which contains a large portion of the genes found on human chromosome 21. Unfortunately, these mice do not survive past birth and thus cannot be used to study the development and function of the nervous system or aging processes. In addition, these mice have extra genes from mouse chromosome 16 that are not triplicated in Down syndrome.

More recent mouse models, such as Ts65Dn, are partially trisomic (3). This means that they contain an extra copy of many, but not all mouse genes equivalent to human chromosome 21. These mice survive to adulthood and express some characteristics of Down syndrome such as developmental delay, hyperactivity, weight problems (4), craniofacial dysmorphology (5), impaired learning, and behavior deficits (6).

Although the current mouse models are quite useful, they do have limitations. For example, the triplicated chromosome or chromosome segments are from a mouse rather than a human. In addition, the triplicated chromosome segments are usually not very long, so they do not represent a complete trisomy. Some of the models contain extra genes that are not found on human chromosome 21, which may lead to anatomical, physical or behavioral changes that are unrelated to Down syndrome.

Scientists are constantly looking to improve mouse models to make them more closely resemble human conditions. We are excited to report that the new mouse model described below is getting us closer to reaching this goal.

A team of scientists in England recently created a new Down syndrome mouse model called Tc1 (Tc = transchromosomic). This mouse carries an almost complete copy of human chromosome 21 (approximately 92% of all genes) and recapitulates several aspects of Down syndrome.

For example, the researchers found that these Tc1 mice have difficulties learning a novel-object recognition task and appear to be slightly more hyperactive than their normal littermates. In addition, long term potentiation - a measurement of learning and memory in the hippocampal brain region - was significantly reduced in Tc1 compared to normal mice.

Because the overall brain size and in particular the cerebellum is smaller in individuals with Down syndrome (7), the researchers took a closer look at the cerebellum of Tc1 mice. They found that the number of cells was indeed reduced in that area of the brain.

Characteristic facial features of people with Down syndrome result primarily from the mal-development of the underlying craniofacial skeleton. Among other distinctions, the mandible (lower jaw) is reduced in people with Down syndrome (8). The researchers found that one aspect of the mandible is also smaller in the Tc1 mouse model.

Lastly, congenital heart defects such as atrioventricular septal defect, ventricular septal defect and atrial septal defect occur in about 40 – 50 % of people with Down syndrome (9). It turns out that the majority of Tc1 mice have heart defects such as perimembranous atrioventricular septal defect or ventricular septal defect. Some mice have a heart tilted onto its right side. This is the first Down syndrome mouse model to mimic these heart defects.

How did the scientists make this mouse?

The Tc1mouse was created using a technique called irradiation microcell-mediated chromosome transfer. Through a series of manipulations, human chromosome 21 was extracted from a donor cell line and individually packaged into small cells. These so-called microcells were fused to recipient mouse embryonic stem cells. The cell containing the largest fragment of chromosome 21 (90%) was chosen for injection into mouse embryos at early stages of development. Subsequently, the embryos were re-implanted into the mother. The resultant mice were mated to normal mice to produce the mouse model now known as Tc1. More than 40% of the litter inherits the human chromosome 21 fragment.

How does the Tc1 mouse differ from other current Down syndrome mouse models?

Current mouse models such as Ts65Dn and Tc1Cje have extra copies of genes from mouse chromosome 16 that correspond to genes on human chromosome 21 (For more details on these mouse models, please refer to a review in News & Views issue 2). These mice are trisomic for a mouse chromosome. In contrast, the new Tc1 mouse contains cells with an almost complete copy of human chromosome 21.

Advantages and disadvantages of using Tc1 mice over current mouse models

The Tc1 mouse includes several genes that are not present in other mice such as Ts65Dn and Tc1Cje. Tc1 is thus a more complete model of Down syndrome. On the other hand, Tc1 lacks a few genes that are present in other models. These might be genes that play an important part in Down syndrome. In addition, it is not clear what the consequences may be of expressing human proteins in a mouse environment.

Tc1 promises to be a good model to study cardiac malformations. None of the other current models mimic Down syndrome heart problems so well.

Perhaps the biggest disadvantage of Tc1 mice is that they are mosaic. This means that not every cell in the Tc1 mouse has a copy of human chromosome 21, i.e. not every cell in the Tc1 mouse is trisomic, and every mouse is different. For certain types of experiments such as measuring physiological activities in the brain, this becomes a tricky issue: It is much harder, more time consuming and more expensive to find out whether the tested cells were trisomic after the experiment rather than from the outset. A higher number of animals and/or cells may be needed in order for the statistics to be meaningful.

In summary, there is no mouse model that perfectly mimics a human condition, because it is after all, a mouse. As is the case with previous mouse models, the Tc1 mouse has its limitations. Nevertheless, Tc1 is a welcome new research tool that in many ways complements the other available mouse models. We are eager to find out what new insights we may gain from these mice.

The article entitled “An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes” by O’Doherty et al. was published in Science (2005), Vol. 309(5743):2003-2037. Read the article's abstract.

See also news coverage by the BCC: story 1 and story 2.

 

References

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

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

Pinter, JD, Eliez, S, Schmitt, JE, Capone, GT, and Reiss, AL (2001) Neuroanatomy of Downs’s Syndrome: A high-resolution MRI study. American Journal of Psychiatry 158:1659-1665

Fink, GB, Madaus, WK, and Walker, GF (1975) A qualitative study of the face in Down’s syndrome. American Journal of Orthodontics 67(5)540-553

Marino, B (1993) Congenital heart disease in patients with Down’s Syndrome: anatomic and genetic aspects. Biomedicine and Pharmacotherapy 47:197-200