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Ts66Yah, a mouse model of Down syndrome with improved construct and face validity
Arnaud Duchon1, Maria Del Mar Muñiz Moreno1, Claire Chevalier1
1Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Translational Medicine and Neurogenetics, 1 rue Laurent Fries, 67404 Illkirch-Graffenstaden, France.
A new mouse model, Ts66Yah, better mimics Down syndrome (DS) cognitive features by isolating chromosome 21 (Hsa21) related genes. This model reveals genetic interactions, improving DS research and therapeutic development.
Area of Science:
- Genetics and Genomics
- Developmental Biology
- Neuroscience
Background:
- Down syndrome (DS) is a genetic disorder caused by trisomy of human chromosome 21 (Hsa21).
- Mouse models are crucial for understanding DS genotype-phenotype relationships and testing therapeutics.
- The Ts65Dn mouse model, a common DS model, contains Hsa21-homologous genes and unrelated genes on a minichromosome.
Purpose of the Study:
- To investigate a new DS mouse model, Ts66Yah, created using CRISPR/Cas9, which excludes non-Hsa21 related genes.
- To compare the construct and face validity of Ts66Yah with the existing Ts65Dn model for Down syndrome research.
- To explore potential genetic interactions between Hsa21-homologous regions and other genomic regions in DS models.
Main Methods:
- Generation of the Ts66Yah mouse model using CRISPR/Cas9 technology.
- Phenotypic analysis of Ts66Yah mice, focusing on cognitive features, activity levels, and spatial learning.
- Molecular signature analysis to identify genetic expression differences.
- Comparison of Ts66Yah phenotypes with those of the Ts65Dn model and human DS features.
Main Results:
- Ts66Yah mice replicated key cognitive features associated with Down syndrome.
- Distinct changes in activity, spatial learning, and molecular signatures were observed in Ts66Yah mice compared to Ts65Dn.
- Evidence suggests genetic interactions between Hsa21-homologous regions and unrelated genomic intervals within the minichromosome.
- Ts66Yah demonstrated improved construct and face validity for modeling Down syndrome genetic overdosage.
Conclusions:
- The Ts66Yah mouse model offers a more precise representation of Down syndrome genetic overdosage effects.
- This study provides the first evidence of genetic interactions between triplicated Hsa21-homologous regions and unrelated genomic segments.
- Ts66Yah serves as a valuable tool for advancing Down syndrome research and the development of targeted therapies.
