eLife (Jun 2020)
A non-mosaic transchromosomic mouse model of Down syndrome carrying the long arm of human chromosome 21
- Yasuhiro Kazuki,
- Feng J Gao,
- Yicong Li,
- Anna J Moyer,
- Benjamin Devenney,
- Kei Hiramatsu,
- Sachiko Miyagawa-Tomita,
- Satoshi Abe,
- Kanako Kazuki,
- Naoyo Kajitani,
- Narumi Uno,
- Shoko Takehara,
- Masato Takiguchi,
- Miho Yamakawa,
- Atsushi Hasegawa,
- Ritsuko Shimizu,
- Satoko Matsukura,
- Naohiro Noda,
- Narumi Ogonuki,
- Kimiko Inoue,
- Shogo Matoba,
- Atsuo Ogura,
- Liliana D Florea,
- Alena Savonenko,
- Meifang Xiao,
- Dan Wu,
- Denise AS Batista,
- Junhua Yang,
- Zhaozhu Qiu,
- Nandini Singh,
- Joan T Richtsmeier,
- Takashi Takeuchi,
- Mitsuo Oshimura,
- Roger H Reeves
Affiliations
- Yasuhiro Kazuki
- ORCiD
- Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan; Chromosome Engineering Research Center (CERC), Tottori University, Yonago, Japan
- Feng J Gao
- ORCiD
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
- Yicong Li
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
- Anna J Moyer
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Genetic Medicine, John Hopkins University School of Medicine, Baltimore, United States
- Benjamin Devenney
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
- Kei Hiramatsu
- Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan
- Sachiko Miyagawa-Tomita
- Department of Animal Nursing Science, Yamazaki University of Animal Health Technology, Hachioji, Tokyo, Japan; Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Satoshi Abe
- Chromosome Engineering Research Center (CERC), Tottori University, Yonago, Japan
- Kanako Kazuki
- Chromosome Engineering Research Center (CERC), Tottori University, Yonago, Japan
- Naoyo Kajitani
- Chromosome Engineering Research Center (CERC), Tottori University, Yonago, Japan
- Narumi Uno
- Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan
- Shoko Takehara
- Chromosome Engineering Research Center (CERC), Tottori University, Yonago, Japan
- Masato Takiguchi
- Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan
- Miho Yamakawa
- Chromosome Engineering Research Center (CERC), Tottori University, Yonago, Japan
- Atsushi Hasegawa
- Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Ritsuko Shimizu
- Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Satoko Matsukura
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
- Naohiro Noda
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
- Narumi Ogonuki
- Bioresource Engineering Division, RIKEN BioResource Research Center (BRC), Tsukuba, Japan
- Kimiko Inoue
- Bioresource Engineering Division, RIKEN BioResource Research Center (BRC), Tsukuba, Japan
- Shogo Matoba
- Bioresource Engineering Division, RIKEN BioResource Research Center (BRC), Tsukuba, Japan
- Atsuo Ogura
- ORCiD
- Bioresource Engineering Division, RIKEN BioResource Research Center (BRC), Tsukuba, Japan
- Liliana D Florea
- Department of Genetic Medicine, John Hopkins University School of Medicine, Baltimore, United States
- Alena Savonenko
- Departments of Pathology and Neurology, John Hopkins University School of Medicine, Baltimore, United States
- Meifang Xiao
- Department of Neuroscience, John Hopkins University School of Medicine, Baltimore, United States
- Dan Wu
- Department of Biomedical Engineering, Zhejiang University, Hangzhou, China
- Denise AS Batista
- Department of Pathology, John Hopkins University School of Medicine, Baltimore, United States
- Junhua Yang
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
- Zhaozhu Qiu
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
- Nandini Singh
- Department of Anthropology, Penn State University, State College, United States
- Joan T Richtsmeier
- ORCiD
- Division of Biosignaling, School of Life Sciences, Faculty of Medicine, Tottori University, Yonago, Japan
- Takashi Takeuchi
- Department of Anthropology, California State University, Sacramento, United States
- Mitsuo Oshimura
- Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan
- Roger H Reeves
- ORCiD
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Genetic Medicine, John Hopkins University School of Medicine, Baltimore, United States
- DOI
- https://doi.org/10.7554/eLife.56223
- Journal volume & issue
-
Vol. 9
Abstract
Animal models of Down syndrome (DS), trisomic for human chromosome 21 (HSA21) genes or orthologs, provide insights into better understanding and treatment options. The only existing transchromosomic (Tc) mouse DS model, Tc1, carries a HSA21 with over 50 protein coding genes (PCGs) disrupted. Tc1 is mosaic, compromising interpretation of results. Here, we “clone” the 34 MB long arm of HSA21 (HSA21q) as a mouse artificial chromosome (MAC). Through multiple steps of microcell-mediated chromosome transfer, we created a new Tc DS mouse model, Tc(HSA21q;MAC)1Yakaz (“TcMAC21”). TcMAC21 is not mosaic and contains 93% of HSA21q PCGs that are expressed and regulatable. TcMAC21 recapitulates many DS phenotypes including anomalies in heart, craniofacial skeleton and brain, molecular/cellular pathologies, and impairments in learning, memory and synaptic plasticity. TcMAC21 is the most complete genetic mouse model of DS extant and has potential for supporting a wide range of basic and preclinical research.
Keywords
