Ts66Yah, a mouse model of Down syndrome with improved construct and face validity

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.

Cognitive and molecular characterization of the Ts66Yah murine model of Down syndrome: deepening on hippocampal changes associated with genotype and aging

“…The genetic validity of available murine models for the study of DS phenotype has been a topic of strong debate in the last decade [3,[33][34][35][36]. To improve the representation of DS human genotype and phenotype in mice, Herault and colleagues developed new line named Ts66Yah, derived from the Ts65Dn lineage but no longer carrying the duplicated centromeric part of Mmu17, [20]. Recent studies compared the phenotype of the Ts66Yah and Ts65Dn mouse models of DS in terms of learning and behaviour, craniofacial and brain morphologies, and gene expression, confirming the interference of Scaf8-Pde10a region trisomy in Ts65Dn.…”

“…Recently, Herault and colleagues developed a new line named Ts66Yah, derived from the Ts65Dn lineage but no longer carrying the duplicated centromeric part of Mmu17 [20]. The Ts66Yah mouse model was generated using CrispR/Cas9 technology in vivo to remove the segment of DNA corresponding to the centromeric Mmu17 located on the Ts65Dn mini chromosome.…”

Hypermetabolism in mice carrying a near complete human chromosome 21

“…Further, the human proteins may alter the stoichiometric compositions of multi-protein complexes in an unpredictable way. For this reason, and for comparison, it is imperative to carry out similar comprehensive metabolic studies in other established DS mouse models (e.g., Dp (16)1Yey/+ and Ts66Yah) where all the trisomic genes are derived from the mouse instead of human, and also without extra trisomic genes not found in Hsa21 (39,40). It is possible the trisomic mouse orthologs of Hsa21 genes are over-expressed and interact with the rest of the mouse genome in a manner that more closely reflects what might be seen in the adipose tissue, liver, and skeletal muscle of DS.…”

Glutamatergic synaptic deficits in the prefrontal cortex of the Ts65Dn mouse model for Down syndrome

“…It is important to note that the Ts65Dn animals have triplication of 50 non-orthologous Mmu17 genes in addition to Mmu16 orthologous genes, which may complicate the genotype/phenotype relationship and contribute to the observed synaptic phenotypes. To address this issue, future experiments could be performed on the refined Ts65Dn model recently developed, the Ts66Yah, which retains the major features of DS, but showed an overall milder phenotype than Ts65Dn mice (Duchon et al, 2022). However, it is worth noting that the partial Ts65Dn model does not overexpress the Hsa21 orthologous genes carried by Mmu10 and Mmu17, which raises questions about the relevance of this partial mouse model as a standard for DS research (Guedj et al, 2022).…”