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Human Molecular Genetics Advance Access published online on January 31, 2006
Human Molecular Genetics, 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@oupjournals.org
Received December 2, 2005
Revised January 25, 2006
Accepted January 25, 2006

Article

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

Atsuko Kasahara 1, Kaori Ishikawa 1, Makiko Yamaoka 2, Masahito Ito 2, Naoki Watanabe 2, Miho Akimoto 2, Akitsugu Sato 2, Kazuto Nakada 1, Hitoshi Endo 3, Yoko Suda 4, Shinichi Aizawa 4, and Jun-Ichi Hayashi1 2 *

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

* To whom correspondence should be addressed.
Jun-Ichi Hayashi1, E-mail: jih45{at}sakura.cc.tsukuba.ac.jp


  Abstract

Generation of various kinds of trans-mitochondrial mice, mito-mice, each carrying mtDNA 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 mtDNA with a T6589C missense mutation in the COI gene (T6589C mtDNA), and the other expressed 40% respiratory activity due to rat mtDNA 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 mtDNA 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 mtDNA were not obtained, suggesting that significant respiration defects or some deficits induced by rat mtDNA in mouse ES cells prevented their differentiation to generate mice carrying rat mtDNA.


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