Cited by 485PI3K/AKT/mTOR signaling in cancerDevelopmental Biology and Gene RegulationReproductive Biology and Fertility

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

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Gangloff, Yann-Gaël, Mueller, Matthias, Dann, Stephen G., Svoboda, Petr, Sticker, Melanie, Spetz, Jean-Francois, Um, Sung Hee, Brown, Eric J. +3 more·2004·Molecular and Cellular Biology

Abstract

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.

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Crossref · 10.1128/mcb.24.21.9508-9516.2004

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  • Treatment of mouse blastocysts with rapamycin or knockout of mTOR causes lethality at E5.5 associated with a failure of trophoblast outgrowth and maintenance of stem cells in the inner cell mass.

    “Indeed, treatment of mouse blastocysts with rapamycin or knockout of mTOR causes lethality at E5.5 associated with a failure of trophoblast outgrowth and maintenance of stem cells in the inner cell mass (206, 360).”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [206]

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Authors
Gangloff, Y.-G., Mueller, M., Dann, S. G., Svoboda, P., Sticker, M., Spetz, J.-F., Um, S. H., Brown, E. J., Cereghini, S., Thomas, G., & Kozma, S. C.
Affiliations
  • University of Cincinnati (US)
  • Novartis (Switzerland) (CH)
  • Friedrich Miescher Institute (CH)
  • Friedrich Miescher Institute for Biomedical Research
  • University of Pennsylvania (US)
  • Centre National de la Recherche Scientifique (FR)
Venue
Molecular and Cellular Biology
Published
2004-11-01
Volume
24
Issue
21
Pages
9508-9516
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
OpenAlex
W2105048034
Cited by
485
References
53
Citations by year
2026: 8 · 2025: 12 · 2024: 13 · 2023: 12 · 2022: 19 · 2021: 36 · 2020: 24 · 2019: 31 · 2018: 24 · 2017: 20 · 2016: 22 · 2015: 19 · 2014: 21 · 2013: 26 · 2012: 36
FWCI
7.24
Type
journal article
Language
en
Open access
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
mTOR, embryonic lethality, postimplantation development, embryonic stem cell differentiation, trophoblast outgrowth, raptors, cell growth regulation
MeSH terms
Alleles, Animals, Cell Differentiation, Cell Division, Cells, Cultured, Female, Fibroblasts, Heterozygote, Pregnancy, Protein Kinases, Stem Cells, Gene Deletion, Mice, Knockout, Embryo Loss, Embryonic Development, Cell Size, Mice, TOR Serine-Threonine Kinases

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