Mouse-based genetic modeling and analysis of Down syndrome

Xing, Zhuo; Li, Yichen; Pao, Annie; Bennett, Abigail S.; Tycko, Benjamin; Mobley, William C.; Yu, Yichao

doi:10.1093/bmb/ldw040

Cited by 25 publications

(14 citation statements)

References 104 publications

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“…; Xing et al. )]. The use of mouse models with Hsa21 homologous genes in three copies has advanced efforts to correlate trisomic genes or regions with DS‐associated phenotypes.…”

Section: The Role Of Ds Mouse Models In Finding Therapiesmentioning

confidence: 99%

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Stringer

Goodlett

Roper

2017

Mol Genet Genomic Med

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Overexpression of Dual‐specificity tyrosine‐phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS‐associated phenotypes have been largely unsuccessful. Epigallocatechin‐3‐gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS‐associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue‐specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue‐specific‐sensitive periods when Dyrk1a regulates cellular processes that shape the long‐term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.

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“…; Xing et al. )]. The use of mouse models with Hsa21 homologous genes in three copies has advanced efforts to correlate trisomic genes or regions with DS‐associated phenotypes.…”

Section: The Role Of Ds Mouse Models In Finding Therapiesmentioning

confidence: 99%

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Stringer

Goodlett

Roper

2017

Mol Genet Genomic Med

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“…Genes on HSA21 are encoded across three mouse chromosomes, and mouse DS models that contain various combinations of orthologous HSA21 genes have been (B) Schematic of chromosome 21 genes that are represented in three mouse models: Ts65Dn (the most widely studied mouse model), Dp16, and Tc1 (a transchromosomic mouse line). [118][119][120] generated 118,119,[141][142][143][144][145][146] (Figure 2). Trisomy 16 mice were originally the most complete HSA21 trisomy model, [147][148][149] but their utility is limited because fetuses do not survive as live-born animals, and so analysis is limited to prenatal development.…”

Section: Unique Geneticsmentioning

confidence: 99%

“…[193][194][195][196][197][198][199][200][201][202][203][204][205][206][207][208] Yet, thorough analyses of all the different trisomic mouse models are still underway, and results are not consistent among models. 142,145,196,204,209 Importantly, the different mouse models have differing or no phenotypes that might link to DS disease characteristics. 210 Although the behavioral phenotypes of some of the DS mouse models could be reminiscent of cognitive characteristics of DS-affected individuals, structural and molecular mechanisms that underlie the phenotypes are different.…”

Section: Modeling Neurological Symptoms and Behavioral Deficitsmentioning

confidence: 99%

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

Zhao

Bhattacharyya

2018

The American Journal of Human Genetics

129

103

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The analysis of animal models of neurological disease has been instrumental in furthering our understanding of neurodevelopment and brain diseases. However, animal models are limited in revealing some of the most fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. These shortcomings are exaggerated in disorders that affect the brain, where the most significant differences between humans and animal models exist, and could underscore failures in targeted therapeutic interventions in affected individuals. Human pluripotent stem cells have emerged as a much-needed model system for investigating human-specific biology and disease mechanisms. However, questions remain regarding whether these cell-culture-based models are sufficient or even necessary. In this review, we summarize human-specific features of neurodevelopment and the most common neurodevelopmental disorders, present discrepancies between animal models and human diseases, demonstrate how human stem cell models can provide meaningful information, and discuss the challenges that exist in our pursuit to understand distinctively human aspects of neurodevelopment and brain disease. This information argues for a more thoughtful approach to disease modeling through consideration of the valuable features and limitations of each model system, be they human or animal, to mimic disease characteristics.

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“…Most models of DS have been based on the homology of Hsa21 and the murine chromosomes (Mmu)16, 17, and 10, or on adding an additional copy of Hsa21 (Deitz & Roper, 2011). Although these mouse lines do not completely resemble DS aneuploidy (Muniz Moreno, Brault, Birling, Pavlovic, & Herault, 2020), they exhibit many DS-like phenotypes, including cognitive, behavioral, molecular, physiological, and neuromorphological alterations (Das & Reeves, 2011;Dierssen, 2012;Rueda, Florez, & Martinez-Cue, 2012;Xing et al, 2016). However, they do not always reproduce DS pathophysiology, probably due to the incomplete synteny between Hsa21 and homologous mouse regions and to the fact that the neural circuitry and plasticity underlying the neural functions of humans are much more complex than those in mice (Benavides-Piccione et al, 2004;Dierssen & Ramakers, 2006).…”

Section: Introductionmentioning

confidence: 99%

Behavioral Phenotyping for Down Syndrome in Mice

et al. 2020

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Down syndrome (DS) is the most frequent genetic cause of intellectual disability, characterized by alterations in different behavioral symptom domains: neurodevelopment, motor behavior, and cognition. As mouse models have the potential to generate data regarding the neurological basis for the specific behavioral profile of DS, and may indicate pharmacological treatments with the potential to affect their behavioral phenotype, it is important to be able to assess disease‐relevant behavioral traits in animal models in order to provide biological plausibility to the potential findings. The field is at a juncture that requires assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this article, behavioral tests are described that are relevant to the domains affected in DS. A neurodevelopmental behavioral screen, the balance beam test, and the Multivariate Concentric Square Field test to assess multiple behavioral phenotypes and locomotion are described, discussing the ways to merge these findings to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Preweaning neurodevelopmental battery Basic Protocol 2: Balance beam Basic Protocol 3: Multivariate concentric square field test (MCSF)

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Mouse-based genetic modeling and analysis of Down syndrome

Abstract: Introduction: Down syndrome (DS), caused by human trisomy 21 (Ts21), can be considered as a prototypical model for understanding the effects of chromosomal aneuploidies in other diseases. Human chromosome 21 (Hsa21) is syntenically conserved with three regions in the mouse genome.

Cited by 25 publications

References 104 publications

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

Behavioral Phenotyping for Down Syndrome in Mice

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