TY - JOUR
T1 - A transchromosomic rat model with human chromosome 21 shows robust Down syndrome features
AU - Kazuki, Yasuhiro
AU - Gao, Feng J.
AU - Yamakawa, Miho
AU - Hirabayashi, Masumi
AU - Kazuki, Kanako
AU - Kajitani, Naoyo
AU - Miyagawa-Tomita, Sachiko
AU - Abe, Satoshi
AU - Sanbo, Makoto
AU - Hara, Hiromasa
AU - Kuniishi, Hiroshi
AU - Ichisaka, Satoshi
AU - Hata, Yoshio
AU - Koshima, Moeka
AU - Takayama, Haruka
AU - Takehara, Shoko
AU - Nakayama, Yuji
AU - Hiratsuka, Masaharu
AU - Iida, Yuichi
AU - Matsukura, Satoko
AU - Noda, Naohiro
AU - Li, Yicong
AU - Moyer, Anna J.
AU - Cheng, Bei
AU - Singh, Nandini
AU - Richtsmeier, Joan T.
AU - Oshimura, Mitsuo
AU - Reeves, Roger H.
N1 - Publisher Copyright:
© 2021 American Society of Human Genetics
PY - 2022/2/3
Y1 - 2022/2/3
N2 - 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.
AB - 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.
KW - Down syndrome
KW - HSA21
KW - TcHSA21rat
KW - TcMAC21
KW - hypoplasia
KW - intellectual disability
KW - rat model
KW - transchromosomic
UR - http://www.scopus.com/inward/record.url?scp=85123781940&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123781940&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2021.12.015
DO - 10.1016/j.ajhg.2021.12.015
M3 - Article
C2 - 35077668
AN - SCOPUS:85123781940
SN - 0002-9297
VL - 109
SP - 328
EP - 344
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -