Molecular characterization of the translocation breakpoints in the Down syndrome mouse model Ts65Dn

Reinholdt, Laura G.; Ding, Yueming; Gilbert, Griffith T.; Czechanski, Anne; Solzak, Jeffrey P.; Roper, Randall J.; Johnson, Mark; Donahue, Leah Rae; Lutz, Cathleen; Davisson, Muriel T.

doi:10.1007/s00335-011-9357-z

Cited by 163 publications

(178 citation statements)

References 18 publications

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“…These individually benign mutations complemented each other in a euploid background: 9.7% of Creld1 +/2 ;Hey2 +/2 mice have septal defects. It has recently been recognized that the freely-segregating marker chromosome that carries these extra Hsa21 orthologous genes in Ts65Dn also contains a third copy of some genes not conserved with Hsa21 (Duchon et al 2011;Reinholdt et al 2011). However, the pattern of septal defects in Ts65Dn is similar to that reported for Dp(16)1Yey mice that carry a direct duplication of all Hsa21 orthologous genes on Mmu16 (Liu et al 2014), albeit at a lower frequency.…”

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confidence: 64%

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Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier

Edie

Klinedinst

et al. 2016

Genetics

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Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart and thus trisomy 21 is not sufficient to cause CHD by itself. Ts65Dn mice are trisomic for orthologs of .100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn increases the penetrance of heart defects significantly. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about two thirds of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1-mediated septal defects in Ts65Dn. Thus, overexpression of the trisomic gene, Jam2, is a necessary potentiator of the disomic genetic modifier, Creld1. No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified, but Jam2 (and its environs) has not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single-gene models.

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confidence: 64%

“…Ts1Rhr and Ts65Dn PCR typing was performed as described (Duchon et al 2011;Reinholdt et al 2011). Genotyping of Creld1 and Jam2 knockout mice was performed by PCR as described (Li et al 2012;Sakaguchi et al 2006).…”

Section: Animal Husbandry and Genotypingmentioning

confidence: 99%

Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier

Edie

Klinedinst

et al. 2016

Genetics

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“…Genotyping was performed on the day of birth. For genotyping, we used primers previously described (Reinholdt et al, 2011). Mutant primers: Chr17fwd-5′-GTGGCAAGAGACTCAAATTCAAC-3′ and Chr16rev-5′-TGGCTTATTATTATCAGGGCATTT-3′.…”

Section: Methodsmentioning

confidence: 99%

Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome

Olmos-Serrano

Tyler

Cabral

et al. 2016

Experimental Neurology

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Mouse models have provided insights into adult changes in learning and memory in Down syndrome, but an in-depth assessment of how these abnormalities develop over time has never been conducted. To address this shortcoming, we conducted a longitudinal behavioral study from birth until late adulthood in the Ts65Dn mouse model to measure the emergence and continuity of learning and memory deficits in individuals with a broad array of tests. Our results demonstrate for the first time that the pace at which neonatal and perinatal milestones are acquired is correlated with later cognitive performance as an adult. In addition, we find that lifelong behavioral indexing stratifies mice within each genotype. Our expanded assessment reveals that diminished cognitive flexibility, as measured by reversal learning, is the most robust learning and memory impairment in both young and old Ts65Dn mice. Moreover, we find that reversal learning degrades with age and is therefore a useful biomarker for studying age-related decline in cognitive ability. Altogether, our results indicate that preclinical studies aiming to restore cognitive function in Ts65Dn should target both neonatal milestones and reversal learning in adulthood. Here we provide the quantitative framework for this type of approach.

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“…The animals employed in this study were produced by two generations of backcrossing. Pups were genotyped to determine the trisomy using standard PCR, as described by Reinholdt et al [24]. In addition, in all the animals the recessive retinal degeneration 1 mutation (Pdebrd1), which is segregating in the colony and results in blindness in homozygotes, was detected by using a standard PCR [25].…”

Section: Methodsmentioning

confidence: 99%

Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome

et al. 2015

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Background: Neurodegenerative diseases are characterized by increased levels of oxidative stress and an altered mammalian target of rapamycin (mTOR)/autophagy axis; however, the mutual relationship between these two events is controversial. Previous studies in Down's syndrome (DS) and Alzheimer's disease (AD) suggested that the accumulation of protein oxidative damage results from the increased free radical production, mainly related to metabolic alterations, mitochondrial degeneration and amyloid-β deposition, and aberrant activity of protein degradative systems. Summary: This study analyzed mTOR signaling in Ts65Dn mice, a model of DS, at 6 and 12 months of age compared with euploid mice showing the early aberrant hyperphosphorylation of mTOR coupled with the reduction of autophagosome formation. Moreover, the evaluation of protein oxidation shows an increase in protein nitration and protein-bound 4-hydroxynonenal in 12-month-old Ts65Dn mice suggesting the potential involvement of altered autophagy in the buildup of protein oxidative damage. In addition, data obtained on cell culture support the protective role of autophagy in reducing protein oxidation. Key Messages: Overall, this study provides further evidence for the role of mTOR hyperactivation and reduced autophagy in the accumulation of protein oxidative damage during DS and AD pathologies.

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Molecular characterization of the translocation breakpoints in the Down syndrome mouse model Ts65Dn

Cited by 163 publications

References 18 publications

Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier

Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier

Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome

Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome

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