Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability.
The rapamycin-insensitive mTOR complex 2 (mTORC2) has been suggested to play an important role in growth factor-dependent signaling. To explore this possibility further in a mammalian model system, we disrupted the expression of rictor, a specific component of mTORC2, in mice by using a multiallelic gene targeting strategy. Embryos that lack rictor develop normally until E9.5, and then exhibit growth arrest and die by E11.5. Although placental defects occur in null embryos, an epiblast-specific knockout of rictor only delayed lethality by a few days, thereby suggesting other important roles for this complex in the embryo proper. Analyses of rictor null embryos and fibroblasts indicate that mTORC2 is a primary kinase for Ser473 of Akt/PKB. Rictor null fibroblasts exhibit low proliferation rates, impaired Akt/PKB activity, and diminished metabolic activity. Taken together, these findings indicate that both rictor and mTORC2 are essential for the development of both embryonic and extraembryonic tissues.
Shiota
Chiyo
C
Department of Molecular Physiology and Biophysics and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Woo
Jeong-Taek
JT
Lindner
Jill
J
Shelton
Kathy D
KD
Magnuson
Mark A
MA
D000199:Actins / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D047109:Fetal Development / Q000235:genetics*; D005328:Fetal Viability / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D018390:Gene Targeting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011494:Protein Kinases / Q000032:analysis / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases
D000199:Actins; D002352:Carrier Proteins; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases