A transchromosomic rat model with human chromosome 21 shows robust Down syndrome features

Abstract

Progress in earlier detection and clinical management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available as a result of technical challenges. We developed a transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein-coding genes. RNA-seq of neonatal forebrains demonstrates that TcHSA21rat expresses HSA21 genes and has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a ''Down syndrome karyotype'' in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, which is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development.

Cortical gradient perturbation in attention deficit hyperactivity disorder correlates with neurotransmitter-, cell type-specific and chromosome- transcriptomic signatures

“…This finding is consistent with prior work identifying variants of chromosome 18 (e.g., 18q11.2-12.3 and 18q21-22) in ADHD patients 96,97 . As the reliable risk factor for the Down syndrome, the chromosome 21 was also linked with ADHD 98,99 , and its duplication could increase risk for neurodevelopmental disorders including ADHD 100 .…”

Neurodevelopment in Down syndrome: Concordance in humans and models

“…However, due to its manner of creation, roughly 50 of the protein coding genes on HSA21 were non-functional and this model was found to be subject to loss of the human chromosome over development creating mosaic mice that were difficult to study (O'Doherty et al, 2005;Gribble et al, 2013). Improvements in technology have circumnavigated this issue by cloning the 34 Mb q arm of HSA21 into a species specific (mouse or rat) artificial chromosome containing the native centromeric region (Kazuki et al, 2020(Kazuki et al, , 2022. The native centromeric region improves chromosome retention and segregation during mitosis and reduces the mosaicism that confounded the Tc1 model.…”

“…The native centromeric region improves chromosome retention and segregation during mitosis and reduces the mosaicism that confounded the Tc1 model. This strategy has been utilized to develop the latest generation mouse model of DS, MAC21 (Kazuki et al, 2020), as well as the first ever rat model of DS, TsHSA21rat (Kazuki et al, 2022). Each of these models contain 93% of the protein coding genes on HSA21 making it the most complete genetic model to date.…”

“…While there have been dozens of mouse models over the years, the first rat model of DS, TcHSA21rat, was recently created and preliminarily described (Kazuki et al, 2022). While still having the benefits of a rodent model including small size, quick gestation time, and experimental malleability, rats are larger and more social than mice.…”

Hypermetabolism in mice carrying a near complete human chromosome 21

“…Both mouse and rat that carry a non-mosaic Hsa21 recapitulate many DS phenotypes related to the central nervous system (e.g., reduced cerebellum volume, learning and memory deficit), craniofacial skeleton, and heart (18, 19). The metabolic phenotype of TcMAC21, however, is unknown and has yet to be examined.…”