Mouse models of aneuploidy to understand chromosome disorders

Tosh, Justin; Tybulewicz, Victor L. J.; Fisher, Elizabeth

doi:10.1007/s00335-021-09930-z

Cited by 22 publications

(11 citation statements)

References 78 publications

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“…The TcMAC21 mouse model overcomes the drawbacks of Tc1 in that it is not mosaic and contains a near complete (93%) Hsa21 [ 63 ]. Of the DS mouse models generated to date, however, only Ts65Dn, Tc1, and TcMAC21 are true aneuploid models with a freely segregating supernumerary chromosome [ 65 ], whereas other DS models have gene dosage imbalance due to intrachromosomal segmental duplications of either mouse chromosome (Mmu)16, Mmu17, or Mmu10 region orthologous to Hsa21 [ 54 ].…”

Section: Introductionmentioning

confidence: 99%

Dysregulated systemic metabolism in a Down syndrome mouse model

Sarver¹,

Xu²,

Veléz³

et al. 2023

Molecular Metabolism

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Section: Introductionmentioning

confidence: 99%

Dysregulated systemic metabolism in a Down syndrome mouse model

Sarver¹,

Xu²,

Veléz³

et al. 2023

Molecular Metabolism

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“…Another approach to modeling DS is to also model the effect of aneuploidy. Models of aneuploidy have also been covered in-depth by others (Tosh et al, 2022 ), but those used in AD-DS preclinical research will be briefly discussed here. The T(171)65Dn (Ts65Dn) mouse model (Davisson et al, 1990 ) has a freely segregating, supernumerary chromosome containing the region Mrpl39-Zfp295 on Mmu16 orthologous to Hsa21 fused with the centromic region of ~10 Mb from Mmu17, resulting in a total of ~90 protein-coding Hsa21 orthologs in three-copies.…”

Section: Mouse Models Of Down Syndromementioning

confidence: 99%

Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches

2022

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There are an estimated 6 million people with Down syndrome (DS) worldwide. In developed countries, the vast majority of these individuals will develop Alzheimer's disease neuropathology characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles within the brain, which leads to the early onset of dementia (AD-DS) and reduced life-expectancy. The mean age of onset of clinical dementia is ~55 years and by the age of 80, approaching 100% of individuals with DS will have a dementia diagnosis. DS is caused by trisomy of chromosome 21 (Hsa21) thus an additional copy of a gene(s) on the chromosome must cause the development of AD neuropathology and dementia. Indeed, triplication of the gene APP which encodes the amyloid precursor protein is sufficient and necessary for early onset AD (EOAD), both in people who have and do not have DS. However, triplication of other genes on Hsa21 leads to profound differences in neurodevelopment resulting in intellectual disability, elevated incidence of epilepsy and perturbations to the immune system. This different biology may impact on how AD neuropathology and dementia develops in people who have DS. Indeed, genes on Hsa21 other than APP when in three-copies can modulate AD-pathogenesis in mouse preclinical models. Understanding this biology better is critical to inform drug selection for AD prevention and therapy trials for people who have DS. Here we will review rodent preclinical models of AD-DS and how these can be used for both in vivo and ex vivo (cultured cells and organotypic slice cultures) studies to understand the mechanisms that contribute to the early development of AD in people who have DS and test the utility of treatments to prevent or delay the development of disease.

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“…In the mouse, Hsa21 orthologous genes map to three syntenic regions on mouse chromosomes (Mmu) 10 (from Pdxk to Prmt2, 2.1 Mb, 39 genes), 16 (from Lipi to Zbtb21, 22.5 Mb, 119 genes) and 17 (from Umodl1 to Rrp1b, 1.1 Mb, 19 genes). Since the Mmu16 region carries the largest number of Hsa21 orthologous genes, it has been used to generate several partial trisomy models, including the Ts(17 16 )65Dn/J (Ts65Dn) mouse (1)(2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

The impact of Mmu17 non-Hsa21 orthologous genes in the Ts65Dn mouse model of Down syndrome: the “gold standard” revisited

Guedj

Kane

Bishop

et al. 2022

Preprint

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Despite many successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome (DS), translation to humans has failed. This raises critical questions about the appropriateness of the Ts65Dn mouse as the gold standard for DS research given that it carries, in addition to Mmu16 orthologous genes, triplication of 50 Mmu17 non-orthologous genes that might contribute to the observed brain and behavioral phenotypes. We used the novel Ts66Yah mouse that carries both an extra mini chromosome and the identical segmental Mmu16 trisomy as Ts65Dn, but in which the Mmu17 non-orthologous region was removed using CRISPR/Cas9 technology. We demonstrate that the Ts65Dn exhibits a more severe phenotype throughout the lifespan compared to the Ts66Yah mouse. Several Mmu17 non-orthologous genes were uniquely overexpressed in Ts65Dn embryonic forebrain; this produced major differences in dysregulated genes and pathways. Despite these genome-wide differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in several commonly dysregulated disomic genes and pathways. During the neonatal period, delays in motor development, communication and olfactory spatial memory were observed in both Ts66Yah and Ts65Dn pups but were more pronounced in Ts65Dn. Adult Ts66Yah mice showed working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved. Like the neonates, adult Ts66Yah mice exhibited fewer and milder behavioral deficits when compared to Ts65Dn mice. Our findings suggest that trisomy of the non-orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may be one major reason why preclinical trials that used this model have unsuccessfully translated to human therapies.

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Mouse models of aneuploidy to understand chromosome disorders

Cited by 22 publications

References 78 publications

Dysregulated systemic metabolism in a Down syndrome mouse model

Dysregulated systemic metabolism in a Down syndrome mouse model

Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches

The impact of Mmu17 non-Hsa21 orthologous genes in the Ts65Dn mouse model of Down syndrome: the “gold standard” revisited

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