Surveying the Down syndrome mouse model resource identifies critical regions responsible for chronic otitis media

Bhutta, Mahmood F.; Cheeseman, Michael; Hérault, Yann; Yu, Yuejin E.; Brown, Steve

doi:10.1007/s00335-013-9475-x

Cited by 9 publications

(9 citation statements)

References 45 publications

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“…This summary is not exhaustive and many additional DS features have been explored using mouse models, such as the mineralisation of long bones ( Blazek et al, 2015 ), the risk of chronic otitis media ( Bhutta et al, 2013 ), and the higher risk of developing myeloproliferative disorders and cancer ( Ng et al, 2015 ; Sussan et al, 2008 ; Malinge et al, 2012 ; Alford et al, 2010 ; Yang et al, 2016 ). Each mouse strain has the potential to provide unique information, and a range of animals, aneuploid and partially trisomic, are important to pinpoint specific candidate genes and dissect the underlying molecular mechanisms.…”

Section: Assessing the Genotype-phenotype Relationship In Dsmentioning

confidence: 99%

Rodent models in Down syndrome research: impact and future opportunities

Hérault

Delabar

Fisher

et al. 2017

Disease Models &Amp; Mechanisms

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165

182

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Down syndrome is caused by trisomy of chromosome 21. To date, a multiplicity of mouse models with Down-syndrome-related features has been developed to understand this complex human chromosomal disorder. These mouse models have been important for determining genotype-phenotype relationships and identification of dosage-sensitive genes involved in the pathophysiology of the condition, and in exploring the impact of the additional chromosome on the whole genome. Mouse models of Down syndrome have also been used to test therapeutic strategies. Here, we provide an overview of research in the last 15 years dedicated to the development and application of rodent models for Down syndrome. We also speculate on possible and probable future directions of research in this fast-moving field. As our understanding of the syndrome improves and genome engineering technologies evolve, it is necessary to coordinate efforts to make all Down syndrome models available to the community, to test therapeutics in models that replicate the whole trisomy and design new animal models to promote further discovery of potential therapeutic targets.

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Section: Assessing the Genotype-phenotype Relationship In Dsmentioning

confidence: 99%

Rodent models in Down syndrome research: impact and future opportunities

Hérault

Delabar

Fisher

et al. 2017

Disease Models &Amp; Mechanisms

Self Cite

165

182

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“… (A) Schematic representation of the triplicated segments of MMU16 in mouse models used in this study. While Ts65Dn mice have triplication of a fragment of MMU16 from Mrp139 to Znf295 , Ts1Cje mice have three copies of a shorter fragment of MMU16 (between Sod1 to Znf295 ) (Bhutta et al, ). Genes triplicated only in T65Dn mice are shown.…”

Section: Introductionmentioning

confidence: 99%

GABAergic hyperinnervation of dentate granule cells in the Ts65Dn mouse model of down syndrome: Exploring the role ofApp

et al. 2016

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It has been suggested that increased GABAergic innervation in the hippocampus plays a significant role in cognitive dysfunction in Down syndrome (DS). Bolstering this notion, are studies linking hyper-innervation of the dentate gyrus (DG) by GABAergic terminals to failure in LTP induction in the Ts65Dn mouse model of DS. Here, we used extensive morphometrical methods to assess the status of GABAergic interneurons in the DG of young and old Ts65Dn mice and their 2N controls. We detected an age-dependent increase in GABAergic innervation of dentate granule cells (DGCs) in Ts65Dn mice. The primary source of GABAergic terminals to DGCs somata is basket cells (BCs). For this reason, we assessed the status of these cells and found a significant increase in the number of BCs in Ts65Dn mice compared with controls. Then we aimed to identify the gene/s whose overexpression could be linked to increased number of BCs in Ts65Dn and found that deleting the third copy of App gene in Ts65Dn mice led to normalization of the number of BCs in these mice. Our data suggest that App overexpression plays a major role in the pathophysiology of GABAergic hyperinnervation of the DG in Ts65Dn mice. © 2016 Wiley Periodicals, Inc.

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“…Animal models can be used to explore the mechanisms underlying conductive, sensorineural, and age-related hearing loss in DS. Most of our efforts and those of others have mainly focused on identifying genomic regions associated with the development of otitis media in DS based on analysis of mouse models triplicated for different Hsa21 orthologous regions (Han et al, 2009 ; Bhutta et al, 2013 ; Chen et al, 2013 ). In Ts65Dn mice, which share many phenotypic characteristics with DS, middle ear effusions were present in nearly 75% of these mice whereas effusions were rare in WT controls.…”

Section: Central Auditory Dysfunctionmentioning

confidence: 99%

Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome

Chen

Xing

Chen³

et al. 2021

Front. Aging Neurosci.

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Down syndrome (DS) is the most common genetic cause of Alzheimer’s disease (AD) due to trisomy for all or part of human chromosome 21 (Hsa21). It is also associated with other phenotypes including distinctive facial features, cardiac defects, growth delay, intellectual disability, immune system abnormalities, and hearing loss. All adults with DS demonstrate AD-like brain pathology, including amyloid plaques and neurofibrillary tangles, by age 40 and dementia typically by age 60. There is compelling evidence that increased APP gene dose is necessary for AD in DS, and the mechanism for this effect has begun to emerge, implicating the C-terminal APP fragment of 99 amino acid (β-CTF). The products of other triplicated genes on Hsa21 might act to modify the impact of APP triplication by altering the overall rate of biological aging. Another important age-related DS phenotype is hearing loss, and while its mechanism is unknown, we describe its characteristics here. Moreover, immune system abnormalities in DS, involving interferon pathway genes and aging, predispose to diverse infections and might modify the severity of COVID-19. All these considerations suggest human trisomy 21 impacts several diseases in an age-dependent manner. Thus, understanding the possible aging-related mechanisms associated with these clinical manifestations of DS will facilitate therapeutic interventions in mid-to-late adulthood, while at the same time shedding light on basic mechanisms of aging.

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Surveying the Down syndrome mouse model resource identifies critical regions responsible for chronic otitis media

Cited by 9 publications

References 45 publications

Rodent models in Down syndrome research: impact and future opportunities

Rodent models in Down syndrome research: impact and future opportunities

GABAergic hyperinnervation of dentate granule cells in the Ts65Dn mouse model of down syndrome: Exploring the role ofApp

Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome

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