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

Dev Cell. 2014 May 12;29(3):321-9. doi: 10.1016/j.devcel.2014.03.017. Epub 2014 Apr 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Embryo, Mammalian / embryology*
  • Hepatocytes / metabolism
  • Liver / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Multiprotein Complexes / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Multiprotein Complexes
  • RagA protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Monomeric GTP-Binding Proteins
  • RagB protein, mouse