Gene Expression Profiling in a Mouse Model of Down Syndrome

( Marc Sultan )

Down syndrome (DS) or trisomy 21 affects 1:700 live births worldwide and represents the major genetic cause of mental retardation in the human population. Over 80 clinical features can occur in DS with considerable variation in the penetrance and severity from one individual to another.

Some of the most relevant questions in DS research are:
1) which of the chr.21 genes, at dosage imbalance, play a role in the phenotype?
2) how the variation of gene expression contributes to the phenotypic variability between individuals?

Owing to the inherent problems limiting the use of human samples, a number of molecular and behavioural studies made use of mouse model of trisomy 21 that parallels some of the phenotypic aspects of DS. Using Ts65Dn, a well-established mouse model of DS, we carried out gene expression profiling by cDNA arrays and quantitative real-time PCR (qRT-PCR).

We focused on the chr.21 genes orthologs because they are the primary contributors of trisomy. We analysed RNAs from several tissues of Ts65Dn and controls, either as pools or as individual samples. With pools, we observed a trend of 1.5 fold overexpression for the majority of trisomic genes with however exceptions to this rule for a few genes (Kahlem et al, 2004).

For many genes, it is unlikely that such a modest change in gene expression levels will have drastic effects on the fitness of the organism. To select genes, where slight changes in gene activity could have a more dramatic phenotypic effect, we focused on the normal variation of gene expression levels. Genes whose level of gene expression is critical are more likely to be tightly controlled than those, for which slight variation of expression will not have a detrimental effect.

Our working hypothesis is that genes relevant for DS reach an expression threshold in trisomic individuals that is not or rarely encountered in controls. Hence, we determined inter-individual expression differences for 50 chr.21 gene orthologs in the cortex, midbrain and cerebellum of individual Ts65Dn mice and controls by qRT-PCR (TaqMan).
Our study enabled the identification of a short list of potential key contributor genes of the trisomy phenotypes in the brain (Sultan et al. submitted).