Modeling Down syndrome in animals from the early stage to the 4.0 models and next

Abstract

Short Abstract (<200 words)The genotype-phenotype relationship and the physiopathology of Down Syndrome (DS) have been explored in the last twenty years with more and more relevant mouse models. From the early age of transgenesis to the new CRISPR/CAS9-derived chromosomal engineering and the transchromosomic technologies, mouse models have been key to identify homologous genes or entire regions homologous to the human chromosome 21 that are necessary or sufficient to induce DS features, to investigate the complexity of the genetic interactions that are involved in DS and to explore therapeutic strategies. In this review we report the new developments made, how genomic data and new genetic tools have deeply changed our way of making models, extended our panel of animal models, and increased our understanding of the neurobiology of the disease. But even if we have made an incredible progress which promises to make DS a curable condition, we are facing new research challenges to nurture our knowledge of DS pathophysiology as a neurodevelopmental disorder with many comorbidities during ageing. Keyword listGenome, animal models, transgenesis, chromosomal engineering, transchromosomic, behaviour and cognition, neurobiology of disease.

Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models

“…Indeed, 15 Hsa21 homologous genes ( Mrpl39, Jam2, Atp5j, Gabpa, App, Cyyr1, Runx1, Setd4, Mx2, Tmprss2, Ripk4, Prdm15, C2cd2 and Zbpb21 ) are not in three copies in Dp5/Dp1 compared with Ts65Dn. In addition 46 protein-coding genes located on the Mmu17 centromeric region in the Ts65Dn minichromosome ( 13 , 16 ) are not trisomic in the Dp5/Dp1. The Dp5Yah model was also combined with Tg( Dyrk1a ) by crossing Dp5Yah/+ and Tg( Dyrk1a )/0 animals and generating the four genotypes (Dp1Yah, Dp5Yah, Tg( Dyrk1 a) and [Dp5Yah; Tg( Dyrk1a )] noted here Dp5-Tg), to test specific interaction between Dp5Yah and Dyrk1a overdosage.…”

“…Indeed, there are three independent mouse regions homologous to Hsa21, carrying altogether 158 protein-coding homologous genes of the 218 protein-coding genes identified on Hsa21 ( 12 ). The largest region is found on mouse chromosome 16 ( Mus musculus 16, noted as Mmu16) in a fragment of 22.42 Mb with 119 orthologous genes between Lipi and Zbtb21 ( 13 ). The most telomeric part is split into two parts.…”

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

“…In the current analysis, we have primarily focused on studies utilizing human DS cells or on clinical studies on DS individuals (as opposed to animal studies). There are, in fact, multiple DS mouse models available (reviewed in Gupta et al 2016 ; Herault et al 2017 ; Muñiz Moreno et al 2020 ), and these models do mimic some of the features of the human DS. However, in mice, the genes that are on human chromosome 21 are localized on 3 different chromosomes, and in most published studies utilizing various DS mice strains use animal models that do not overexpress all of the human-DS genes.…”

All Creatures Great and Small: New Approaches for Understanding Down Syndrome Genetics

“…Since the introduction of Ts65Dn, more than 20 mouse models have been generated to study the effects of trisomy of Hsa21 genes or their mouse orthologs. The gene content and limitations of extant DS mouse models have been reviewed extensively elsewhere [12,81,82]. Here, we discuss three emerging opportunities for creating new murine models that may better reflect the genetic basis of trisomy 21: mouse artificial chromosome models, induced pluripotent stem cell (iPSC) models, and rat models.…”