title: mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells.
abstract: 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.
authors.affiliation: Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Nara 630-0192, Japan.
authors.forename: Mirei
authors.initials: M
authors.lastname: Murakami
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ichisaka
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Maeda
authors.forename: Noriko
authors.initials: N
authors.lastname: Oshiro
authors.forename: Kenta
authors.initials: K
authors.lastname: Hara
authors.forename: Frank
authors.initials: F
authors.lastname: Edenhofer
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyama
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yonezawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D015139:Blotting, Southern; D002453:Cell Cycle; D002455:Cell Division; D004622:Embryo, Mammalian / Q000166:cytology*; D005434:Flow Cytometry; D017353:Gene Deletion; D005838:Genotype; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D009154:Mutation; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D011494:Protein Kinases; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus