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: (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 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 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.

New approaches to studying early brain development in Down syndrome

“…Hsa21 contains 222 protein coding genes, and 325 non‐protein encoding genes . Studies of partial trisomy of Hsa21 have revealed that multiple regions of Hsa21 contribute to the observed physical and neurodevelopmental characteristics of Down syndrome .…”

“…Mouse models of Down syndrome have been crucial to help investigate the genetic and developmental origins of the Down syndrome phenotype and importantly to test therapies that have the potential to improve neurogenesis and long‐term cognition . Hsa21 shares synteny with a large proportion of mouse chromosome (Mmu) 16 (approximately 102 protein coding genes) and shorter regions of Mmu10 (37 protein coding genes) and Mmu17 (19 protein coding genes) . These have all been key targets in generating mouse models of Down syndrome (for a comprehensive list of mouse models of Down syndrome see Herault et al …”

“…The Ts65Dn mouse (B6EiC3Sn a / A ‐Ts[17 16 ]65Dn/J) has historically been very important in the study of Down syndrome as it is trisomic for 90 protein coding genes on Mmu16 (approximately 55% of orthologous genes to Hsa21). However, Ts65Dn mice contain an extra copy of 60 genes (35 protein coding) located on Mmu17 (orthologous to Hsa6) that are not triplicated in people with Down syndrome and the resultant Ts65Dn phenotypes may be more severe than those seen in the human condition or possess spurious phenotypes not relevant to Down syndrome . Other mouse strains have therefore been developed with partial trisomy of genes on Mmu16.…”

Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

“…2) Down syndrome is caused by a triplication of chromosome 21, incorporating a third copy of approximately 300 genes (Holtzman and Epstein 1992; Hattori et al, 2000; Chapman et al, 2000; Gardiner et al, 2010; Dierssen, 2012; Kleschevnikov et al, 2012). Ts65Dn mice with partial trisomy of the syntenic genes on mouse chromosome 16, originally generated by Reeves, Davisson and co-workers (Reeves et al, 1995), display behavioral abnormalities including deficits in water maze hidden platform acquisition, novel object recognition and radial maze, and higher exploration in an open field and on an elevated plus-maze (Reeves et al, 1995; Coussons-Read and Crnic, 1996; Demas et al, 1996; Sago et al, 2000; Moran et al, 2002; Martinez-Cue et al, 2005; Costa et al, 2010; Das and Reeves, 2011; Braudeau et al, 2011; Cramer and Galdzicki, 2012; Velazquez et al, 2013; Smith et al, 2014; Gupta et al, 2016). 3) Rett syndrome is caused by a mutation in MECP2 on the X chromosome, which codes for the epigenetic methylation regulator methyl-CpG-binding protein (Amir et al, 1999; Lombardi et al, 2015).…”

Changing Paradigms in Down Syndrome: The First International Conference of the Trisomy 21 Research Society

“…Gardiner reviewed the gene content of HSA21, emphasizing what is now known about long noncoding RNA genes and the conservation of protein-coding genes in orthologous mouse genomic regions [Gupta et al, 2016]. She also presented new data on the extensive differences in protein expression in several brain regions between male and female DS mice trisomic for the HSA21 orthologous region on mouse chromosome 10 (MMU10).…”