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A non-mosaic transchromosomic mouse model of Down syndrome carrying the long arm of human chromosome 21

  1. Yasuhiro Kazuki  Is a corresponding author
  2. Feng J Gao
  3. Yicong Li
  4. Anna J Moyer
  5. Benjamin Devenney
  6. Kei Hiramatsu
  7. Sachiko Miyagawa-Tomita
  8. Satoshi Abe
  9. Kanako Kazuki
  10. Naoyo Kajitani
  11. Narumi Uno
  12. Shoko Takehara
  13. Masato Takiguchi
  14. Miho Yamakawa
  15. Atsushi Hasegawa
  16. Ritsuko Shimizu
  17. Satoko Matsukura
  18. Naohiro Noda
  19. Narumi Ogonuki
  20. Kimiko Inoue
  21. Shogo Matoba
  22. Atsuo Ogura
  23. Liliana D Florea
  24. Alena Savonenko
  25. Meifang Xiao
  26. Dan Wu
  27. Denise AS Batista
  28. Junhua Yang
  29. Zhaozhu Qiu
  30. Nandini Singh
  31. Joan T Richtsmeier
  32. Takashi Takeuchi
  33. Mitsuo Oshimura
  34. Roger H Reeves  Is a corresponding author
  1. Tottori University, Japan
  2. Johns Hopkins University School of Medicine, United States
  3. Yamazaki University of Animal Health Technology, Japan
  4. Tohoku University Graduate School of Medicine, Japan
  5. National Institute of Advanced Industrial Science and Technology, Japan
  6. RIKEN BioResource Research Center, Japan
  7. Zhejiang University, China
  8. John Hopkins University School of Medicine, United States
  9. California State University, United States
  10. Pennsylvania State University, United States
Research Article
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Cite this article as: eLife 2020;9:e56223 doi: 10.7554/eLife.56223

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.

Article and author information

Author details

  1. Yasuhiro Kazuki

    Institute of Regenerative Medicine and Biofunction, Tottori University, Yonago, Japan
    For correspondence
    kazuki@tottori-u.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
  2. Feng J Gao

    Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yicong Li

    Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Anna J Moyer

    Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Benjamin Devenney

    Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kei Hiramatsu

    Institute of Regenerative Medicine and Biofunction, Tottori University, Yonago, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Sachiko Miyagawa-Tomita

    Yamazaki University of Animal Health Technology, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Satoshi Abe

    Chromosome Engineering Research Center, Tottori University, Yonago, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Kanako Kazuki

    Chromosome Engineering Research Center, Tottori University, Yonago, Japan
    Competing interests
    The authors declare that no competing interests exist.
  10. Naoyo Kajitani

    Chromosome Engineering Research Center, Tottori University, Yonago, Japan
    Competing interests
    The authors declare that no competing interests exist.
  11. Narumi Uno

    Institute of Regenerative Medicine and Biofunction, Tottori University, Yonago, Japan
    Competing interests
    The authors declare that no competing interests exist.
  12. Shoko Takehara

    Chromosome Engineering Research Center, Tottori University, Yonago, Japan
    Competing interests
    The authors declare that no competing interests exist.
  13. Masato Takiguchi

    Institute of Regenerative Medicine and Biofunction, Tottori University, Yonago, Japan
    Competing interests
    The authors declare that no competing interests exist.
  14. Miho Yamakawa

    Chromosome Engineering Research Center, Tottori University, Yonago, Japan
    Competing interests
    The authors declare that no competing interests exist.
  15. Atsushi Hasegawa

    Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan
    Competing interests
    The authors declare that no competing interests exist.
  16. Ritsuko Shimizu

    Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan
    Competing interests
    The authors declare that no competing interests exist.
  17. Satoko Matsukura

    Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  18. Naohiro Noda

    Biomedical Research, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  19. Narumi Ogonuki

    Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  20. Kimiko Inoue

    Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  21. Shogo Matoba

    Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  22. Atsuo Ogura

    Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0447-1988
  23. Liliana D Florea

    Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Alena Savonenko

    Pathology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Meifang Xiao

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  26. Dan Wu

    Department of Biomedical Engineering, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  27. Denise AS Batista

    Pathology, John Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  28. Junhua Yang

    Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  29. Zhaozhu Qiu

    Pathology, John Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  30. Nandini Singh

    Department of Anthropology, California State University, Sacramento, United States
    Competing interests
    The authors declare that no competing interests exist.
  31. Joan T Richtsmeier

    Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0239-5822
  32. Takashi Takeuchi

    Division of Biosignaling, Tottori University, Yonago, Japan
    Competing interests
    The authors declare that no competing interests exist.
  33. Mitsuo Oshimura

    Department of Biomedical Science, Tottori University, Yonago, Japan
    Competing interests
    The authors declare that no competing interests exist.
  34. Roger H Reeves

    Department of Physiology and Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    rreeves@jhmi.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3581-0850

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.

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)..

Reviewing Editor

  1. Susan L Ackerman, Howard Hughes Medical Institute, University of California, San Diego, United States

Publication history

  1. Received: February 20, 2020
  2. Accepted: June 28, 2020
  3. Accepted Manuscript published: June 29, 2020 (version 1)

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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