Rheb1 is required for mTORC1 and myelination in postnatal brain development.
mTor kinase is involved in cell growth, proliferation, and differentiation. The roles of mTor activators, Rheb1 and Rheb2, have not been established in vivo. Here, we report that Rheb1, but not Rheb2, is critical for embryonic survival and mTORC1 signaling. Embryonic deletion of Rheb1 in neural progenitor cells abolishes mTORC1 signaling in developing brain and increases mTORC2 signaling. Remarkably, embryonic and early postnatal brain development appears grossly normal in these Rheb1f/f,Nes-cre mice with the notable exception of deficits of myelination. Conditional expression of Rheb1 transgene in neural progenitors increases mTORC1 activity and promotes myelination in the brain. In addition the Rheb1 transgene rescues mTORC1 signaling and hypomyelination in the Rheb1f/f,Nes-cre mice. Our study demonstrates that Rheb1 is essential for mTORC1 signaling and myelination in the brain, and suggests that mTORC1 signaling plays a role in selective cellular adaptations, rather than general cellular viability.
The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
Jia
J
Zou
Liang
L
Zhou
Xiao-Xia
XX
Du
Yifei
Y
Ji
Jia
J
Xu
Junlong
J
Tian
Wanxiang
W
Jiang
Yi
Y
Zou
Shouyang
S
Yu
Lingxue
L
Gan
Maowen
M
Luo
Qiaona
Q
Yang
Yiyuan
Y
Cui
Wanchun
W
Yang
Xiaoqiang
X
Xia
Mina
M
Chen
Xia
X
Zhao
Ying
Y
Shen
Po Yu
PY
Chen
Paul F
PF
Worley
Bo
B
Xiao
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D017353:Gene Deletion; D019426:Integrases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes; D050505:Mutant Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D019076:Transgenes / Q000235:genetics
D000596:Amino Acids; D036341:Intercellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D009479:Neuropeptides; D011506:Proteins; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C045073:Cre recombinase; D019426:Integrases; D020559:Monomeric GTP-Binding Proteins
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