RagA, but not RagB, is essential for embryonic development and adult mice.
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.
Whitehead 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.
Alejo
A
Efeyan
Whitehead 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.
Lawrence D
LD
Schweitzer
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Angelina M
AM
Bilate
Whitehead 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.
Steven
S
Chang
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Oktay
O
Kirak
Whitehead 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.
Dudley W
DW
Lamming
Whitehead 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.
David M
DM
Sabatini
D000818:Animals; D002460:Cell Line; D004622:Embryo, Mammalian / Q000196:embryology*; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C000589375:Rraga protein, Mouse; C000589376:Rragb protein, Mouse