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Molecular and Cellular Biology, August 2004, p. 6710-6718, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6710-6718.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

mTOR Is Essential for Growth and Proliferation in Early Mouse Embryos and Embryonic Stem Cells

Mirei Murakami,1,2 Tomoko Ichisaka,1,2 Mitsuyo Maeda,3 Noriko Oshiro,2,4 Kenta Hara,2,5 Frank Edenhofer,6 Hiroshi Kiyama,3 Kazuyoshi Yonezawa,2,4* and Shinya Yamanaka1,2*

Research and Education Center for Genetic Information, Nara Institute of Science and Technology,1 CREST, Japan Science and Technology Agency, Nara 630-0192,2 Department of Anatomy and Neurobiology, Osaka City University Medical School, Osaka 545-8585,3 Biosignal Research Institute, Kobe University, Hyogo 657-8501,4 Fourth Department of Internal Medicine, Kobe University School of Medicine, Hyogo 650-0017, Japan,5 Institute of Reconstructive Neurobiology, University of Bonn Medical Center, D-53105 Bonn, Germany6

Received 7 January 2004/ Returned for modification 21 March 2004/ Accepted 11 May 2004

TOR is a serine-threonine kinase that was originally identified as a target of rapamycin in Saccharomyces cerevisiae and then found to be highly conserved among eukaryotes. In Drosophila melanogaster, inactivation of TOR or its substrate, S6 kinase, results in reduced cell size and embryonic lethality, indicating a critical role for the TOR pathway in cell growth control. However, the in vivo functions of mammalian TOR (mTOR) remain unclear. In this study, we disrupted the kinase domain of mouse mTOR by homologous recombination. While heterozygous mutant mice were normal and fertile, homozygous mutant embryos died shortly after implantation due to impaired cell proliferation in both embryonic and extraembryonic compartments. Homozygous blastocysts looked normal, but their inner cell mass and trophoblast failed to proliferate in vitro. Deletion of the C-terminal six amino acids of mTOR, which are essential for kinase activity, resulted in reduced cell size and proliferation arrest in embryonic stem cells. These data show that mTOR controls both cell size and proliferation in early mouse embryos and embryonic stem cells.

* Corresponding author. Mailing address: Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Nara 630-0192, Japan. Phone: 743725591. Fax: 743725591. E-mail for Kazuyoshi Yonezawa: yonezawa{at}kobe-u.ac.jp. E-mail for Shinya Yamanaka: shinyay{at}gtc.naist.ac.jp.

Molecular and Cellular Biology, August 2004, p. 6710-6718, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6710-6718.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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