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Mouse models of Down syndrome: gene content and consequences
Meenal Gupta1, A Ranjitha Dhanasekaran1, Katheleen J Gardiner2,3,4
1Department of Pediatrics, Linda Crnic Institute for Down Syndrome, University of Colorado Denver School of Medicine, Aurora, CO, USA.
Summary
Developing accurate mouse models for Down syndrome (DS) is complex due to gene mapping differences. This study evaluates existing DS mouse models, comparing their trisomic gene content to human chromosome 21 for better preclinical drug testing.
Area of Science:
- Genetics
- Developmental Biology
- Pharmacology
Background:
- Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21).
- Modeling DS in mice is challenging due to the complex mapping of Hsa21 gene orthologs across multiple mouse chromosomes.
- Existing mouse models, like Ts65Dn, have limitations in accurately representing full trisomy 21.
Purpose of the Study:
- To review and analyze the trisomic gene content of various Down syndrome mouse models.
- To assess the strengths and weaknesses of current DS mouse models for preclinical drug evaluation.
- To provide a framework for interpreting results from DS mouse models in relation to full trisomy 21.
Main Methods:
- Review of functional information on Hsa21 protein-coding and RNA genes.
- Analysis of conservation and genomic distribution of Hsa21 orthologs in the mouse genome.
- Comparative assessment of trisomic gene content across different DS mouse models.
Main Results:
- Hsa21 orthologs are distributed across Mmu16, Mmu17, and Mmu10 in the mouse genome.
- The Ts65Dn model, while useful, is trisomic for only a subset of Hsa21 orthologs and includes non-Hsa21 orthologs.
- Multiple DS mouse models exist, each with varying trisomic gene profiles.
Conclusions:
- A comprehensive understanding of gene content in DS mouse models is crucial for interpreting preclinical data.
- Careful selection and validation of DS mouse models are necessary for effective drug development for Down syndrome.
- Further refinement of DS mouse models is needed to better recapitulate the genetic landscape of human trisomy 21.
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