Ts66Yah, an upgraded Ts65Dn mouse model for Down syndrome, for only the region homologous to Human chromosome 21

Abstract

Down syndrome is caused by trisomy of human chromosome 21 (Hsa21). The understanding of phenotype-genotype relationships, the identification of driver genes and various proof-of-concepts for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to the human DS features. It carries an additional minichromosome with the Mir155 to Zbtb21 region of mouse chromosome 16 (Mmu16), homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 (Mmu17) fromPisd-ps2/Scaf8 to Pde10a, containing 46 genes, not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CrispR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures, were changed suggesting genetic interactions between the Mir155-Zbtb21 and the Scaf8-Pde10a interval. Thus, Ts66Yah mice have a stronger construct and face validity for mimicking consequences of DS genetic overdosage. Furthermore, this report is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21.

Dysregulated systemic metabolism in a Down syndrome mouse model

“…The presence of 46 trisomic protein-coding genes in the centromeric region of Mmu17 that are unrelated to Hsa21 may complicate the genotype–phenotype relationship. To circumvent this major limitation, CRISPR/Cas9-based genome editing approach has recently been used to remove the 46 genes from the Mmu17 centromeric region of the marker chromosome [ 159 ]. Behavioral and neurocognitive characterization of the refined Ts66Yah mice (trisomic for only Mmu16 genes) showed the conservation of key DS features, but with an overall milder phenotype compared to Ts65Dn mice [159] , [160] .…”

“…To circumvent this major limitation, CRISPR/Cas9-based genome editing approach has recently been used to remove the 46 genes from the Mmu17 centromeric region of the marker chromosome [ 159 ]. Behavioral and neurocognitive characterization of the refined Ts66Yah mice (trisomic for only Mmu16 genes) showed the conservation of key DS features, but with an overall milder phenotype compared to Ts65Dn mice [159] , [160] . It should be noted that a modified Ts65Dn strain, 5252, which shows attenuated severity of phenotypes compared to its original version and to the original Ts65Dn strain, was used to create Ts66Yah.…”