RagA, but not RagB, is essential for embryonic development and adult mice.
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Abstract | The mechanistic target of rapamycin complex 1 (mTORC1) integrates cues from growth factors and nutrients to control metabolism. In contrast to the growth factor input, genetic disruption of nutrient-dependent activation of mTORC1 in mammals remains unexplored. We engineered mice lacking RagA and RagB genes, which encode the GTPases responsible for mTORC1 activation by nutrients. RagB has limited expression, and its loss shows no effects on mammalian physiology. RagA deficiency leads to E10.5 embryonic death, loss of mTORC1 activity, and severe growth defects. Primary cells derived from these mice exhibit no regulation of mTORC1 by nutrients and maintain high sensitivity to growth factors. Deletion of RagA in adult mice is lethal. Upon RagA loss, a myeloid population expands in peripheral tissues. RagA-specific deletion in liver increases cellular responses to growth factors. These results show the essentiality of nutrient sensing for mTORC1 activity in mice and its suppression of PI3K/Akt signaling. |
Year of Publication | 2014
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Journal | Dev Cell
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Volume | 29
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Issue | 3
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Pages | 321-9
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Date Published | 2014 May 12
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ISSN | 1878-1551
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URL | |
DOI | 10.1016/j.devcel.2014.03.017
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PubMed ID | 24768164
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PubMed Central ID | PMC4035553
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Links | |
Grant list | R01 AI047389 / AI / NIAID NIH HHS / United States
R01 CA103866 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
F31CA167872 / CA / NCI NIH HHS / United States
F31 CA167872 / CA / NCI NIH HHS / United States
R00 AG041765 / AG / NIA NIH HHS / United States
AI047389 / AI / NIAID NIH HHS / United States
CA103866 / CA / NCI NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
R21 AG042876 / AG / NIA NIH HHS / United States
Howard Hughes Medical Institute / United States
AG041765 / AG / NIA NIH HHS / United States
R01 CA129105 / CA / NCI NIH HHS / United States
K99 AG041765 / AG / NIA NIH HHS / United States
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