Cited by 41Down syndrome and intellectual disability researchWilliams Syndrome ResearchGenetics and Neurodevelopmental Disorders

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

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Kazuki, Yasuhiro, Gao, Feng J., Yamakawa, Miho, Hirabayashi, Masumi, Kazuki, Kanako, Kajitani, Naoyo, Miyagawa-Tomita, Sachiko, Abe, Satoshi +20 more·2022·The American Journal of Human Genetics

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.

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Crossref · 10.1016/j.ajhg.2021.12.015

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  • TcHSA21rat exhibit learning and memory deficits and other cardinal features of DS such as craniofacial changes and cardiovascular deficits.

    “Similar to the MAC21 mouse, TcHSA21rat exhibit learning and memory deficits as well as other cardinal features of DS such as craniofacial changes and cardiovascular deficits.”

    From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Kazuki et al., 2022

  • TcHSA21rat recapitulates the decrease in total brain volume characteristic of DS, and the cerebellum is specifically decreased in size with a simpler foliation pattern.

    “Opposed to current mouse models of DS, the TcHSA21rat model recapitulates the decrease in total brain volume that is characteristics in DS. In addition, the cerebellum is specifically decreased in size compared to euploid controls and has a simpler foliation pattern, a feature that is unable to be observed in mouse models.”

    From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Kazuki et al., 2022

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  1. [18]18. [Braudeau, J., Delatour, B., Duchon, A., Pereira, P.L., Dauphinot, L., de Chaumont, F., Olivo-Marin, J.C., Dodd, R.H., He ´rault, Y., and Potier, M.C. (2011). Specific targeting of the GABA-A receptor a 5 subtype by a selective inverse agonist re-](http://refhub.elsevier.com/S0002-9297(21)00470-5/sref18)
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Authors
Kazuki, Y., Gao, F. J., Yamakawa, M., Hirabayashi, M., Kazuki, K., Kajitani, N., Miyagawa-Tomita, S., Abe, S., Sanbo, M., Hara, H., Kuniishi, H., Ichisaka, S., Hata, Y., Koshima, M., Takayama, H., Takehara, S., Nakayama, Y., Hiratsuka, M., Iida, Y., Matsukura, S., Noda, N., Li, Y., Moyer, A. J., Cheng, B., Singh, N., Richtsmeier, J. T., Oshimura, M., & Reeves, R. H.
Affiliations
  • Chromosome Engineering Research Center (JP)
  • Johns Hopkins University (US)
  • National Institute for Physiological Sciences (JP)
  • Trans Chromosomics, Inc. (Japan) (JP)
  • Tottori University (JP)
  • National Institute of Advanced Industrial Science and Technology (JP)
  • California State University, Sacramento (US)
  • Pennsylvania State University (US)
Corresponding author
  • Kazuki, Yasuhiro
  • Reeves, Roger H.
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2022-02
Volume
109
Issue
2
Pages
328-344
ISSN
0002-9297 (ISSN-L)
OpenAlex
W4206983653
Cited by
41
References
74
Citations by year
2026: 7 · 2025: 7 · 2024: 11 · 2023: 13 · 2022: 3
FWCI
7.51
Type
journal article
Language
en
Open access
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
Funders
  • Mitsubishi Foundation (R01HD038384, R21HD098540)
  • Core Research for Evolutional Science and Technology (JPMJCR18S4)
  • National Institutes of Health (R21HD098540, R01HD038384)
  • Japan Science and Technology Agency
  • National Institute for Physiological Sciences (17-252)
  • National Institute of Advanced Industrial Science and Technology
  • Tottori University
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Down syndrome, chromosome 21, trisomy, rat model, cerebellar foliation, learning and memory impairment, anxiety, hyperactivity, brain structure, craniofacial anomalies, heart development, gene expression imbalance, preclinical drug development
MeSH terms
Animals, Anxiety, Cerebellum, Chromosomes, Human, Pair 21, Disease Models, Animal, Down Syndrome, Female, Humans, Hyperkinesis, Learning, Male, Organ Size, Posture, Mutagenesis, Insertional, Prosencephalon, Genes, Reporter, Founder Effect, Green Fluorescent Proteins, Rats, Rats, Transgenic, Karyotype

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