Rodent models in Down syndrome research: impact and future opportunities

Abstract

Down syndrome is caused by trisomy of chromosome 21. To date, a multiplicity of mouse models with Down-syndrome-related features has been developed to understand this complex human chromosomal disorder. These mouse models have been important for determining genotype-phenotype relationships and identification of dosage-sensitive genes involved in the pathophysiology of the condition, and in exploring the impact of the additional chromosome on the whole genome. Mouse models of Down syndrome have also been used to test therapeutic strategies. Here, we provide an overview of research in the last 15 years dedicated to the development and application of rodent models for Down syndrome. We also speculate on possible and probable future directions of research in this fast-moving field. As our understanding of the syndrome improves and genome engineering technologies evolve, it is necessary to coordinate efforts to make all Down syndrome models available to the community, to test therapeutics in models that replicate the whole trisomy and design new animal models to promote further discovery of potential therapeutic targets.

Keywords: Aneuploidy; Chromosome engineering; Dosage-senstive gene; Down syndrome; Mouse model.

Fig. 1.

Mouse models of DS. Human chromosome 21 (p and q arms; G-banding) is depicted at the top of the figure, with the mouse genome orthologous region found on chromosome 16 (Mmu16), Mmu10 and Mmu17 shown respectively in orange, light green and red. A few known genes that are homologous to Hsa21 genes in the DS critical region are listed below each chromosome. The transchromosomic Tc1 mouse model is shown in dark green, with deletions and a duplication (double bar) relative to Hsa21 depicted. Below, the segment of the DS critical region encompassed in different mouse models for DS is illustrated. The original Ts65Dn (Reeves et al., 1995) and Ts1Cje (Sago et al., 1998) models (shown in brown) originated by accidental translocation of Mmu16 segments respectively on Mmu17 and Mmu12, with some additional changes (Duchon et al., 2011b; Reinholdt et al., 2011). Olson et al. (2004) published the first engineered duplication (Dp) and deletion [deficiency (Df)] for the DS critical region (light blue). New models have been developed in the last 10 years by the authors of this Review, as shown in dark blue (Duchon et al., 2011a; Lopes Pereira et al., 2009; Besson et al., 2007; Marechal et al., 2015; Sahun et al., 2014; Raveau et al., 2012; Arbogast et al., 2015; Brault et al., 2015b), red (Jiang et al., 2015; Liu et al., 2011, 2014; Yu et al., 2010a,b,c; Li et al., 2007) and green (Lana-Elola et al., 2016). TgBACs, a few models for BAC or PAC (P1-derived artificial chromosome) transgenic lines.

Fig. 2.

Cre-loxP-mediated chromosomal engineering in mice. A loxP site (arrow) is targeted into the first endpoint of the engineered segment (blue) in the embryonic stem (ES) cell genome with a positive selectable marker, such as neo (the neomycin-resistance gene; N). Next, a second loxP site is targeted to the other endpoint with another positive selectable marker such as puro, the puromycin resistance gene (P). A Cre expression vector is then transferred by electroporation into double-targeted ES cell clones. If two loxP sites are targeted onto the same chromosome homologue and oriented in the same direction (cis), recombination between the sites will lead to a deletion (Df; A). If two loxP sites are targeted onto two separate homologues and oriented in the same direction (trans), the recombination will lead to a duplication (Dp) and the reciprocal deletion (Df) (B).