Abnormal mineralization of the Ts65Dn Down syndrome mouse appendicular skeleton begins during embryonic development in a Dyrk1a-independent manner

Blazek, J; Malik, Aatika; Tischbein, Maeve; Arbonés, María L.; Moore, Clara S.; Roper, Randall J.

doi:10.1016/j.mod.2014.12.004

Cited by 24 publications

(19 citation statements)

References 37 publications

(51 reference statements)

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“…This proposition is supported by ultrasound bone measurements at 11–14 weeks of gestation showing short femur lengths in fetuses with trisomy 21 24 . Abnormal bone development in trisomy 21 is thought to originate from genotype–phenotype interaction during embryonic development 5 . The differences between our sample and the WHO norms varied by age, with a large standard deviation score occurring during the first months of life.…”

Section: Discussionsupporting

confidence: 69%

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Growth charts for Brazilian children with Down syndrome: Birth to 20 years of age

Bertapelli

Agiovlasitis

Machado

et al. 2017

Journal of Epidemiology

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BackgroundThe growth of youth with Down syndrome (DS) differs from that of youth without DS, and growth charts specific to DS have been developed. However, little is known about the growth of Brazilian youth with DS. The objective of this study was to construct growth charts for Brazilian youth with DS and compare the growth data with the Child Growth Standards of the World Health Organization (WHO) and charts for children with DS from other studies.MethodsMixed longitudinal and cross-sectional data were collected at University of Campinas, 48 specialized centers for people with intellectual disabilities, and two foundations for people with DS between 2012 and 2015. A total of 10,516 growth measurements from birth to 20 years of age were available from 938 youth with DS (53.7% boys) born between 1980 and 2013. The Lambda Mu Sigma method was applied to construct the curves using generalized additive models for location, scale, and shape.ResultsLength/height-for-age, weight-for-age, and head circumference-for-age percentile curves were generated for Brazilian boys and girls from birth to 20 years of age. Differences in growth of Brazilian youth ranged from −0.8 to −3.2 z-scores compared to WHO standards, and −1.9 to +1.3 compared to children with DS in other studies.ConclusionsThese specific growth charts may guide clinicians and families in monitoring the growth of Brazilian children and adolescents with DS.

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Section: Discussionsupporting

confidence: 69%

“…Children with DS have different growth patterns compared to children without DS 3, 4. Abnormal bone development is the most common feature and is hypothesized to be regulated by genetic factors 5 . A review showed that stature of children with DS was 0.4–4.0 standard deviations below that of children without DS 6 .…”

Section: Introductionmentioning

confidence: 99%

Growth charts for Brazilian children with Down syndrome: Birth to 20 years of age

Bertapelli

Agiovlasitis

Machado

et al. 2017

Journal of Epidemiology

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“…Aside from the change in ultimate stress with treatment, all mechanical changes were in whole bone properties which suggest that it was mostly changes in bone size/geometry that drove mechanical deficits as compared to inferior tissue quality. Similar skeletal deficits including decreases in ultimate force and stiffness were quantified in femurs from euploid mice with only one copy of Dyrk1a [63]. …”

Section: Discussionmentioning

confidence: 83%

“…In contrast, our previous study using a three week administration of EGCG (~10mg/kg/day) showed improved skeletal deficits including femoral bone mineral density, percent trabecular bone volume, trabecular number and trabecular thickness in Ts65Dn mice [63]. These results suggest that in bone, there may be an “inverted U” function of optimal Dyrk1a activity, such that an optimal range of activity is necessary to achieve maximum skeletal strength, and falling below the threshold (as with high doses of EGCG) or exceeding an upper boundary (as with excess activity in trisomy) may be detrimental to bone strength.…”

Section: Discussionmentioning

confidence: 87%

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Stringer

Abeysekera

Thomas

et al. 2017

Physiology & Behavior

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Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~10mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~20mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2–3 mg per day (~40–60mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4 mg/mL] or a water control, with treatments yielding average daily intakes of ~50 mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)—which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking—and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone.

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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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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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Abnormal mineralization of the Ts65Dn Down syndrome mouse appendicular skeleton begins during embryonic development in a Dyrk1a-independent manner

Cited by 24 publications

References 37 publications

Growth charts for Brazilian children with Down syndrome: Birth to 20 years of age

Growth charts for Brazilian children with Down syndrome: Birth to 20 years of age

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Rodent models in Down syndrome research: impact and future opportunities

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