Mouse models of Down syndrome: gene content and consequences

Abstract

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is challenging to model in mice. Not only is it a contiguous gene syndrome spanning 35 Mb of the long arm of Hsa21, but orthologs of Hsa21 genes map to segments of three mouse chromosomes, Mmu16, Mmu17, and Mmu10. The Ts65Dn was the first viable segmental trisomy mouse model for DS; it is a partial trisomy currently popular in preclinical evaluations of drugs for cognition in DS. Limitations of the Ts65Dn are as follows: (i) it is trisomic for 125 human protein-coding orthologs, but only 90 of these are Hsa21 orthologs and (ii) it lacks trisomy for ~75 Hsa21 orthologs. In recent years, several additional mouse models of DS have been generated, each trisomic for a different subset of Hsa21 genes or their orthologs. To best exploit these models and interpret the results obtained with them, prior to proposing clinical trials, an understanding of their trisomic gene content, relative to full trisomy 21, is necessary. Here we first review the functional information on Hsa21 protein-coding genes and the more recent annotation of a large number of functional RNA genes. We then discuss the conservation and genomic distribution of Hsa21 orthologs in the mouse genome and the distribution of mouse-specific genes. Lastly, we consider the strengths and weaknesses of mouse models of DS based on the number and nature of the Hsa21 orthologs that are, and are not, trisomic in each, and discuss their validity for use in preclinical evaluations of drug responses.

Figure 1. Distribution of protein coding genes within 21q

A schematic of a Giemsa banded Hsa21q is shown at the left. The total number of (non-Krtap) protein coding genes and numbers within several functional classes are provided for syntenic regions on mouse chromosome 16 (Mmu16), Mmu17 and Mmu10. Syntenic regions are demarcated by horizontal solid or dashed lines; similar numbers for the sub region of Mmu16 trisomic in the Ts65Dn are shown shaded. TF, transcription factors; Ubi, members of the ubiquitin pathway; RNA, proteins involved in RNA processing; AD, proteins directly relevant to Alzheimer’s Disease or involved in processing or trafficking of the Hsa21 encoded protein APP (amyloid precursor protein). For functional annotations, see Supplementary Table S1.

Figure 2. Trisomic regions and number of non-KRTAP protein coding genes trisomic in mouse models of DS

Blue, yellow, green: Hsa21 syntenic regions on Mmu16, 17 and 10, respectively. Numbers in brackets indicate the number of conserved protein coding genes that are trisomic. The Hsa6 syntenic region in the Ts65Dn is indicated by stripes and contains 35 protein coding genes. Grey ovals within the Tc1 chromosome indicate major deletions. Arrows indicate location of Dyrk1A and Kcnj6 within Mmu16.