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 InoueShogo Matoba, Atsuo Ogura, Liliana D. Florea, Alena Savonenko, Meifang Xiao, Dan Wu, Denise A.S. Batista, Junhua Yang, Zhaozhu Qiu, Nandini Singh, Joan T. Richtsmeier, Takashi Takeuchi, Mitsuo Oshimura, Roger H. Reeves

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere56223
Pages (from-to)1-29
Number of pages29
JournaleLife
Volume9
DOIs
StatePublished - Jun 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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