This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gangloff, Y.-G.
Right arrow Articles by Kozma, S. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gangloff, Y.-G.
Right arrow Articles by Kozma, S. C.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2004, p. 9508-9516, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9508-9516.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Disruption of the Mouse mTOR Gene Leads to Early Postimplantation Lethality and Prohibits Embryonic Stem Cell Development

Yann-Gaël Gangloff,1,{dagger} Matthias Mueller,2 Stephen G. Dann,3 Petr Svoboda,1 Melanie Sticker,1 Jean-Francois Spetz,1 Sung Hee Um,1 Eric J. Brown,4 Silvia Cereghini,5 George Thomas,1 and Sara C. Kozma1,3*

Friedrich Miescher Institute for Biomedical Research,1 Novartis Institute for BioMedical Research, Novartis Pharma AG, Basel, Switzerland,2 Genome Research Institute, University of Cincinnati, Cincinnati, Ohio,3 Department of Cancer Biology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,4 Biologie du Développement, UMR 7622, CNRS, Université Pierre et Marie Curie, Paris, France5

Received 2 August 2004/ Accepted 10 August 2004

The mammalian target of rapamycin (mTOR) is a key component of a signaling pathway which integrates inputs from nutrients and growth factors to regulate cell growth. Recent studies demonstrated that mice harboring an ethylnitrosourea-induced mutation in the gene encoding mTOR die at embryonic day 12.5 (E12.5). However, others have shown that the treatment of E4.5 blastocysts with rapamycin blocks trophoblast outgrowth, suggesting that the absence of mTOR should lead to embryonic lethality at an earlier stage. To resolve this discrepancy, we set out to disrupt the mTOR gene and analyze the outcome in both heterozygous and homozygous settings. Heterozygous mTOR (mTOR+/–) mice do not display any overt phenotype, although mouse embryonic fibroblasts derived from these mice show a 50% reduction in mTOR protein levels and phosphorylation of S6 kinase 1 T389, a site whose phosphorylation is directly mediated by mTOR. However, S6 phosphorylation, raptor levels, cell size, and cell cycle transit times are not diminished in these cells. In contrast to the situation in mTOR+/– mice, embryonic development of homozygous mTOR–/– mice appears to be arrested at E5.5; such embryos are severely runted and display an aberrant developmental phenotype. The ability of these embryos to implant corresponds to a limited level of trophoblast outgrowth in vitro, reflecting a maternal mRNA contribution, which has been shown to persist during preimplantation development. Moreover, mTOR–/– embryos display a lesion in inner cell mass proliferation, consistent with the inability to establish embryonic stem cells from mTOR–/– embryos.

* Corresponding author. Mailing address: Genome Research Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237. Phone: (513) 558-8112. Fax: (513) 558-5061. E-mail: sara.kozma{at}uc.edu.

{dagger} Present address: Equipe Différenciation Neuromusculaire, UMR 5161, CNRS, Ecole Normale Supérieure, F-69364 Lyon Cedex 07, France.

Molecular and Cellular Biology, November 2004, p. 9508-9516, Vol. 24, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.21.9508-9516.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chen, X., He, J., Ding, Y., Zeng, L., Gao, R., Cheng, S., Liu, X., Wang, Y. (2009). The role of MTOR in mouse uterus during embryo implantation. Reproduction 138: 351-356 [Abstract] [Full Text]  
  • Bazer, F. W, Spencer, T. E, Johnson, G. A, Burghardt, R. C, Wu, G. (2009). Comparative aspects of implantation. Reproduction 138: 195-209 [Abstract] [Full Text]  
  • Geest, C. R., Zwartkruis, F. J., Vellenga, E., Coffer, P. J., Buitenhuis, M. (2009). Mammalian target of rapamycin activity is required for expansion of CD34+ hematopoietic progenitor cells. haematol 94: 901-910 [Abstract] [Full Text]  
  • Zhou, J., Su, P., Wang, L., Chen, J., Zimmermann, M., Genbacev, O., Afonja, O., Horne, M. C., Tanaka, T., Duan, E., Fisher, S. J., Liao, J., Chen, J., Wang, F. (2009). mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells. Proc. Natl. Acad. Sci. USA 106: 7840-7845 [Abstract] [Full Text]  
  • Nardella, C., Carracedo, A., Alimonti, A., Hobbs, R. M., Clohessy, J. G., Chen, Z., Egia, A., Fornari, A., Fiorentino, M., Loda, M., Kozma, S. C., Thomas, G., Cordon-Cardo, C., Pandolfi, P. P. (2009). Differential Requirement of mTOR in Postmitotic Tissues and Tumorigenesis. Sci Signal 2: ra2-ra2 [Abstract] [Full Text]  
  • Kim, M.-S., Kuehn, H. S., Metcalfe, D. D., Gilfillan, A. M. (2008). Activation and Function of the mTORC1 Pathway in Mast Cells. J. Immunol. 180: 4586-4595 [Abstract] [Full Text]  
  • Yang, X., Yang, C., Farberman, A., Rideout, T. C., de Lange, C. F. M., France, J., Fan, M. Z. (2008). The mammalian target of rapamycin-signaling pathway in regulating metabolism and growth. J ANIM SCI 86: E36-E50 [Abstract] [Full Text]  
  • Jindra, P. T., Hsueh, A., Hong, L., Gjertson, D., Shen, X.-D., Gao, F., Dang, J., Mischel, P. S., Baldwin, W. M. III, Fishbein, M. C., Kupiec-Weglinski, J. W., Reed, E. F. (2008). Anti-MHC Class I Antibody Activation of Proliferation and Survival Signaling in Murine Cardiac Allografts. J. Immunol. 180: 2214-2224 [Abstract] [Full Text]  
  • Fosslien, E. (2008). Cancer Morphogenesis: Role of Mitochondrial Failure. Annals of Clinical & Laboratory Science 38: 307-330 [Abstract] [Full Text]  
  • Buitenhuis, M., Verhagen, L. P., van Deutekom, H. W. M., Castor, A., Verploegen, S., Koenderman, L., Jacobsen, S.-E. W., Coffer, P. J. (2008). Protein kinase B (c-akt) regulates hematopoietic lineage choice decisions during myelopoiesis. Blood 111: 112-121 [Abstract] [Full Text]  
  • Jossin, Y., Goffinet, A. M. (2007). Reelin Signals through Phosphatidylinositol 3-Kinase and Akt To Control Cortical Development and through mTor To Regulate Dendritic Growth. Mol. Cell. Biol. 27: 7113-7124 [Abstract] [Full Text]  
  • van den Boom, V., Kooistra, S. M., Boesjes, M., Geverts, B., Houtsmuller, A. B., Monzen, K., Komuro, I., Essers, J., Drenth-Diephuis, L. J., Eggen, B. J.L. (2007). UTF1 is a chromatin-associated protein involved in ES cell differentiation. JCB 178: 913-924 [Abstract] [Full Text]  
  • Mieulet, V., Roceri, M., Espeillac, C., Sotiropoulos, A., Ohanna, M., Oorschot, V., Klumperman, J., Sandri, M., Pende, M. (2007). S6 kinase inactivation impairs growth and translational target phosphorylation in muscle cells maintaining proper regulation of protein turnover. Am. J. Physiol. Cell Physiol. 293: C712-C722 [Abstract] [Full Text]  
  • Roos, S., Jansson, N., Palmberg, I., Saljo, K., Powell, T. L., Jansson, T. (2007). Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth. J. Physiol. 582: 449-459 [Abstract] [Full Text]  
  • Moumen, A., Patane, S., Porras, A., Dono, R., Maina, F. (2007). Met acts on Mdm2 via mTOR to signal cell survival during development. Development 134: 1443-1451 [Abstract] [Full Text]  
  • Weisman, R., Roitburg, I., Schonbrun, M., Harari, R., Kupiec, M. (2007). Opposite Effects of Tor1 and Tor2 on Nitrogen Starvation Responses in Fission Yeast. Genetics 175: 1153-1162 [Abstract] [Full Text]  
  • Wang, X., Proud, C. G. (2006). The mTOR Pathway in the Control of Protein Synthesis.. Physiology 21: 362-369 [Abstract] [Full Text]  
  • Jankiewicz, M., Groner, B., Desrivieres, S. (2006). Mammalian Target of Rapamycin Regulates the Growth of Mammary Epithelial Cells through the Inhibitor of Deoxyribonucleic Acid Binding Id1 and Their Functional Differentiation through Id2. Mol. Endocrinol. 20: 2369-2381 [Abstract] [Full Text]  
  • Wang, J., Wang, N., Xie, J., Walton, S. C., McKown, R. L., Raab, R. W., Ma, P., Beck, S. L., Coffman, G. L., Hussaini, I. M., Laurie, G. W. (2006). Restricted epithelial proliferation by lacritin via PKC{alpha}-dependent NFAT and mTOR pathways. JCB 174: 689-700 [Abstract] [Full Text]  
  • Cota, D., Proulx, K., Smith, K. A. B., Kozma, S. C., Thomas, G., Woods, S. C., Seeley, R. J. (2006). Hypothalamic mTOR signaling regulates food intake.. Science 312: 927-930 [Abstract] [Full Text]  
  • Wenzlau, J. M., Garl, P. J., Simpson, P., Stenmark, K. R., West, J., Artinger, K. B., Nemenoff, R. A., Weiser-Evans, M. C.M. (2006). Embryonic Growth-Associated Protein Is One Subunit of a Novel N-Terminal Acetyltransferase Complex Essential for Embryonic Vascular Development. Circ. Res. 98: 846-855 [Abstract] [Full Text]  
  • Van Winkle, L. J., Tesch, J. K., Shah, A., Campione, A. L. (2006). System B0,+ amino acid transport regulates the penetration stage of blastocyst implantation with possible long-term developmental consequences through adulthood. Hum Reprod Update 12: 145-157 [Abstract] [Full Text]  
  • Maloney, C. A, Rees, W. D (2005). Gene-nutrient interactions during fetal development. Reproduction 130: 401-410 [Abstract] [Full Text]  
  • Park, I.-H., Chen, J. (2005). Mammalian Target of Rapamycin (mTOR) Signaling Is Required for a Late-stage Fusion Process during Skeletal Myotube Maturation. J. Biol. Chem. 280: 32009-32017 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»