An Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes

O’Doherty, Aideen; Ruf, Sandra; Mulligan, Catherine; Hildreth, Victoria; Errington, Mick L.; Cooke, Sam; Sesay, Abdul Karim; Modino, Sonie; Vanes, Lesley; Hernandez, Diana; Linehan, Jacqueline M.; Sharpe, Paul T.; Brandner, Sebastian; Bliss, T. V. P.; Henderson, Deborah J.; Nižetić, Dean; Tybulewicz, Victor L. J.; Fisher, Elizabeth

doi:10.1126/science.1114535

Cited by 393 publications

(510 citation statements)

References 39 publications

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“…Hspa13 transgenic mice. Although the Tc1 model overexpresses HSPA13, this is a modest increase in expression (×2) of the human protein and the known mosaicism suggests that this is not present in all neurons (19). More importantly, this model overexpresses many additional human genes from Hsa21, making it difficult to ascribe any difference in incubation time directly to HSPA13 overexpression.…”

Section: Resultsmentioning

confidence: 99%

“…1); therefore, we looked at overexpression models. Hspa13 is located on mouse chromosome 16 (Mmu16), with its human homolog on human chromosome 21 (Hsa21); thus, it is likely to be overexpressed in the Tc(Hsa21) 1TybEmcf (Tc1) transchromosomic mouse model of Down syndrome (19). The Tc1 mouse contains a normal mouse diploid genome and an additional freely segregating almost complete Hsa21.…”

Section: Resultsmentioning

confidence: 99%

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Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

Grizenkova

Akhtar

Hummerich

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins, which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period, we tested two overexpressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/Rocky Mountain Laboratory (RML) prion inoculation, shows a 4% reduction in incubation time. Furthermore, a transgenic model with eightfold overexpression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16, 15, and 7% following infection with Chandler/RML, ME7, and MRC2 prion strains, respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

Grizenkova

Akhtar

Hummerich

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Mouse ES cells containing fragments of human chromosomes 2, 14 and 22 showed tissue specific expression of the human genes in chimeric mice, suggesting a whole chromosome might also exhibit expression in the mouse (Tomizuka, et al 1997). MMCT that was used to generate a mouse model of Down syndrome recapitulated the phenotype, providing further evidence for transcriptional activity of human chromosomes in nuclei from different species (O'Doherty, et al 2005). …”

Section: Transcriptional Activity Of Human Chromosomes In Mouse-humanmentioning

confidence: 95%

Position of human chromosomes is conserved in mouse nuclei indicating a species-independent mechanism for maintaining genome organization

et al. 2008

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The non-random positioning of chromosome territories in eukaryotic cells is largely correlated with gene density and is conserved throughout evolution. Gene rich chromosomes are predominantly central while gene poor chromosomes are peripherally localized in interphase nuclei. We previously demonstrated that artificially introduced human chromosomes assume a position equivalent to their endogenous homologues in the diploid colon cancer cell line DLD-1. These chromosomal aneuploidies result in a significant increase in transcript levels, suggesting a relationship between genomic copy number, gene expression and chromosome position. We previously proposed that each chromosome is marked by a "zip-code" that determines its non-random position in the nucleus. Here we investigated (1) whether mouse nuclei recognize such determinants of nuclear position on human chromosomes to facilitate their distinct partitioning and (2) if chromosome positioning and transcriptional activity remain coupled under these trans-species conditions. Using 3D-FISH, confocal microscopy and gene expression profiling, we show (i) that gene poor and gene rich human chromosomes maintain their divergent but conserved positions in mouse-human hybrid nuclei and (ii) that a foreign human chromosome is actively transcribed in mouse nuclei. Our results suggest a species-independent conserved mechanism for the non-random positioning of chromosomes in the 3-dimensional interphase nucleus.

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“…Thus, more complete models are required. One such model that was reported recently 101 is a mouse that carries a human chromosome 21. Drawbacks to this model, in addition to being a heterologous system, are that the mice are mosaics (not all cells in an individual contain the extra chromosome, and the proportions of trisomic cells vary among mice).…”

Section: Mouse Modelsmentioning

confidence: 99%

The cognitive phenotype of Down syndrome: Insights from intracellular network analysis

2006

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Summary: Down syndrome (DS) is caused by trisomy of chromosome 21. All individuals with DS exhibit some level of cognitive dysfunction. It is generally accepted that these abnormalities are a result of the upregulation of genes encoded by chromosome 21. Many chromosome 21 proteins are known or predicted to function in critical neurological processes, but typically they function as modulators of these processes, not as key regulators. Thus, upregulation in DS is expected to cause only modest perturbations of normal processes. Systematic approaches such as intracellular network construction and analysis have not been generally applied in DS research. Networks can be assembled from highthroughput experiments or by text-mining of experimental literature. We survey some new developments in constructing such networks, focusing on newly developed network analysis methodologies. We propose how these methods could be integrated with creation and manipulation of mouse models of DS to advance our understanding of the perturbed cell signaling pathways in DS. This understanding could lead to potential therapeutics.

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An Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes

Cited by 393 publications

References 39 publications

Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

Position of human chromosomes is conserved in mouse nuclei indicating a species-independent mechanism for maintaining genome organization

The cognitive phenotype of Down syndrome: Insights from intracellular network analysis

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