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.
- Roger H Reeves
- Roger H Reeves
- Mitsuo Oshimura
- Yasuhiro Kazuki
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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)..
- Susan L Ackerman, Howard Hughes Medical Institute, University of California, San Diego, United States
- Received: February 20, 2020
- Accepted: June 28, 2020
- Accepted Manuscript published: June 29, 2020 (version 1)
© 2020, Kazuki et al.
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