A non-mosaic transchromosomic mouse model of Down syndrome carrying the long arm of human chromosome 21
- Tottori University, Japan
- Johns Hopkins University School of Medicine, United States
- Yamazaki University of Animal Health Technology, Japan
- Tohoku University Graduate School of Medicine, Japan
- National Institute of Advanced Industrial Science and Technology, Japan
- RIKEN BioResource Research Center, Japan
- Zhejiang University, China
- John Hopkins University School of Medicine, United States
- California State University, United States
- Pennsylvania State University, United States
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.
Data availability
All raw read data of TcMAC21 WGS were deposited to DDBJ Sequence Read Archive (DRA) under accession number DRA008337 and DRA008342
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Analysis of DS mouseDDBJ Sequence Read Archive (DRA) ,DRA008337.
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Analysis of DS mouseDDBJ Sequence Read Archive (DRA), DRA008342.
Article and author information
Author details
Joan T Richtsmeier
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD098540-01)
- Roger H Reeves
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD038384)
- Roger H Reeves
Japan Society for the Promotion of Science (25221308)
- Mitsuo Oshimura
Core Research for Evolutional Science and Technology (JPMJCR18S4)
- Yasuhiro Kazuki
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Susan L Ackerman, Howard Hughes Medical Institute, University of California, San Diego, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) protocols of Johns Hopkins University (#MO18M291), Tottori University (Permit Number: 06-S-102, 08-Y-69, 09-Y-24,11-Y-52, 13-Y-19, 14-Y-23, 15-Y-31, 16-Y-20, 17-Y-28, 19-Y-22, 20-Y-13), RIKEN BioResource Research Center (Permit Number: 08-005, 09-005, 10-005), and Tohoku University (Permit Number: 2013MdA-424)..
Version history
- Received: February 20, 2020
- Accepted: June 28, 2020
- Accepted Manuscript published: June 29, 2020 (version 1)
- Version of Record published: July 13, 2020 (version 2)
- Version of Record updated: July 14, 2020 (version 3)
Copyright
© 2020, Kazuki et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A non-mosaic transchromosomic mouse model of Down syndrome carrying the long arm of human chromosome 21
eLife 9:e56223.
https://doi.org/10.7554/eLife.56223
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