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

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  • Mirei Murakami
    Research and Education Center for Genetic Information, Nara Institute of Science and Technology
  • Tomoko Ichisaka
    Research and Education Center for Genetic Information, Nara Institute of Science and Technology
  • Mitsuyo Maeda
    Department of Anatomy and Neurobiology, Osaka City University Medical School, Osaka 545-8585
  • Noriko Oshiro
    CREST, Japan Science and Technology Agency, Nara 630-0192
  • Kenta Hara
    CREST, Japan Science and Technology Agency, Nara 630-0192
  • Frank Edenhofer
    Institute of Reconstructive Neurobiology, University of Bonn Medical Center, D-53105 Bonn, Germany
  • Hiroshi Kiyama
    Department of Anatomy and Neurobiology, Osaka City University Medical School, Osaka 545-8585
  • Kazuyoshi Yonezawa
    CREST, Japan Science and Technology Agency, Nara 630-0192
  • Shinya Yamanaka
    Research and Education Center for Genetic Information, Nara Institute of Science and Technology

説明

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.

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