Format

Send to

Choose Destination
See comment in PubMed Commons below
Dev Cell. 2014 May 12;29(3):321-9. doi: 10.1016/j.devcel.2014.03.017. Epub 2014 Apr 24.

RagA, but not RagB, is essential for embryonic development and adult mice.

Author information

  • 1Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA.
  • 2Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
  • 3Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA. Electronic address: sabatini@wi.mit.edu.

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk