Rodent models in Down syndrome research: impact and future opportunities

Abstract

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.

New approaches to studying early brain development in Down syndrome

“…Advances in genome‐wide analysis and the development of animal models have provided valuable insight into understanding gene dosage imbalances in disorders such as Down syndrome . Mouse models of Down syndrome have been crucial to help investigate the genetic and developmental origins of the Down syndrome phenotype and importantly to test therapies that have the potential to improve neurogenesis and long‐term cognition . Hsa21 shares synteny with a large proportion of mouse chromosome (Mmu) 16 (approximately 102 protein coding genes) and shorter regions of Mmu10 (37 protein coding genes) and Mmu17 (19 protein coding genes) .…”

“…Hsa21 shares synteny with a large proportion of mouse chromosome (Mmu) 16 (approximately 102 protein coding genes) and shorter regions of Mmu10 (37 protein coding genes) and Mmu17 (19 protein coding genes) . These have all been key targets in generating mouse models of Down syndrome (for a comprehensive list of mouse models of Down syndrome see Herault et al …”

“…The Tc1 (B6129S‐Tc[HSA21]1TybEmcf/J) transchromosomic (trans‐species aneuploidy) mouse line contains a freely segregated copy of Hsa21. Although some chromosomal rearrangement and deletions have been identified in the construction process, it has allowed exploration of the relationship between specific Hsa21 genes (including those not found in the mouse) and phenotype . Whilst amyloid precursor protein (APP) is known to significantly contribute to the early‐onset of Alzheimer disease, recently it has been shown that triplication of other genes on Hsa21 (Tc1 mouse is 75% trisomic for Hsa21 genes) can exacerbate plaque formation and cognitive deficits in mice .…”

GATA1 and cooperating mutations in myeloid leukaemia of Down syndrome

“…The underlying molecular mechanisms driving these changes have been challenging to study in vivo —in part because orthologues of human chromosome 21 map to segments of three different mouse chromosomes (Mmu16, 17, and 10). A number of elegant DS mouse models have been generated (reviewed in Reference ). Although none of these models fully recapitulate the haematopoietic abnormalities seen in human T21, they have provided valuable insights into potential contributors to ML‐DS pathogenesis .…”

CRISPR/Cas9-Facilitated Chromosome Engineering to Model Human Chromosomal Alterations

“…Phenotypic characterizations of this mutant revealed several important DS-related phenotypes, including heart defects and impaired cognitive function. Other engineered mouse mutants, which carry a triplication or deiciency of smaller Hsa21 syntenic regions [5,6], have facilitated systematic genetic dissections of DS phenotypes. With the emergence of CRISPR/Cas9-facilitated genome editing, atempts have been made to further improve the eiciency of mammalian chromosome manipulations, whether it be deletions, duplications, inversions, or translocations [7][8][9][10], including those in Hsa21 syntenic regions.…”