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Human Molecular Genetics Advance Access originally published online on January 31, 2006
Human Molecular Genetics 2006 15(6):871-881; doi:10.1093/hmg/ddl005
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© The Author 2006. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oxfordjournals.org

Generation of trans-mitochondrial mice carrying homoplasmic mtDNAs with a missense mutation in a structural gene using ES cells

Atsuko Kasahara1,2, Kaori Ishikawa1,2, Makiko Yamaoka1, Masahito Ito1, Naoki Watanabe1, Miho Akimoto1, Akitsugu Sato1, Kazuto Nakada1,2, Hitoshi Endo3, Yoko Suda4, Shinichi Aizawa4 and Jun-Ichi Hayashi1,*

1Graduate School of Life and Environmental Sciences, Institute of Biological Sciences and 2Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Ibaraki 305-8572, Japan, 3Department of Biochemistry, Jichi Medical School, Tochigi 329-0498, Japan and 4Laboratory for Vertebrate Body Plan, Center for Developmental Biology (CDB), RIKEN Kobe, Kobe 650-0047, Japan

* To whom correspondence should be addressed at: Graduate School of Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8572, Japan. Tel: +81 298536650; Fax: +81 298536650; Email: jih45{at}sakura.cc.tsukuba.ac.jp

Received December 2, 2005; Accepted January 25, 2006

Generation of various kinds of trans-mitochondrial mice, mito-mice, each carrying mtDNAs with a different pathogenic mutation, is required for precise investigation of the pathogenesis of mitochondrial diseases. This study used two respiration-deficient mouse cell lines as donors of mtDNAs with possible pathogenic mutations. One cell line expressed 45–50% respiratory activity due to mouse mtDNAs with a T6589C missense mutation in the COI gene (T6589C mtDNA) and the other expressed 40% respiratory activity due to rat (Rattus norvegicus) mtDNAs in mouse cells. By cytoplasmic transfer of these mtDNAs to mouse ES cells, we isolated respiration-deficient ES cells. We obtained chimeric mice and generated their F6 progeny carrying mouse T6589C mtDNAs by its female germ line transmission. They were respiration-deficient and thus could be used as models of mitochondrial diseases caused by point mutations in mtDNA structural genes. However, chimeric mice and mito-mice carrying rat mtDNAs were not obtained, suggesting that significant respiration defects or some deficits induced by rat mtDNAs in mouse ES cells prevented their differentiation to generate mice carrying rat mtDNAs.


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