mTORC1 Targets the Translational Repressor 4E-BP2, but Not S6 Kinase 1/2, to Regulate Neural Stem Cell Self-Renewal In Vivo

• Published in: Cell reports (Cambridge) Vol. 5; no. 2; pp. 433 - 444
• Main Authors: Hartman, Nathaniel W., Lin, Tiffany V., Zhang, Longbo, Paquelet, Grace E., Feliciano, David M., Bordey, Angélique
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.10.2013; Elsevier
• Subjects: Animals; Carrier Proteins - metabolism; Cell Differentiation - drug effects; Cells, Cultured; Eukaryotic Initiation Factors - antagonists & inhibitors; Eukaryotic Initiation Factors - genetics; Eukaryotic Initiation Factors - metabolism; Mechanistic Target of Rapamycin Complex 1; Mice; Monomeric GTP-Binding Proteins - antagonists & inhibitors; Monomeric GTP-Binding Proteins - genetics; Monomeric GTP-Binding Proteins - metabolism; Multiprotein Complexes - metabolism; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neuropeptides - antagonists & inhibitors; Neuropeptides - genetics; Neuropeptides - metabolism; Phosphoproteins - metabolism; Phosphorylation - drug effects; Ras Homolog Enriched in Brain Protein; Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 90-kDa - genetics; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.09.017

The mammalian target of rapamycin complex 1 (mTORC1) integrates signals important for cell growth, and its dysregulation in neural stem cells (NSCs) is implicated in several neurological disorders associated with abnormal neurogenesis and brain size. However, the function of mTORC1 on NSC self-renewal and the downstream regulatory mechanisms are ill defined. Here, we found that genetically decreasing mTORC1 activity in neonatal NSCs prevented their differentiation, resulting in reduced lineage expansion and aborted neuron production. Constitutive activation of the translational repressor 4E-BP1, which blocked cap-dependent translation, had similar effects and prevented hyperactive mTORC1 induction of NSC differentiation and promoted self-renewal. Although 4E-BP2 knockdown promoted NSC differentiation, p70 S6 kinase 1 and 2 (S6K1/S6K2) knockdown did not affect NSC differentiation but reduced NSC soma size and prevented hyperactive mTORC1-induced increase in soma size. These data demonstrate a crucial role of mTORC1 and 4E-BP for switching on and off cap-dependent translation in NSC differentiation. [Display omitted] •mTORC1 loss of function limits NSC differentiation and neuron production•mTORC1 gain of function induces NSC differentiation at the expense of self-renewal•4E-BP2, but not S6K1/S6K2, mediates mTORC1-induced NSC differentiation•Differential 4E-BP2 and S6K1/S6K2 roles in NSC self-renewal and growth Neural stem cells (NSCs) lie at the core of brain development and repair. Bordey and colleagues report that the mammalian target of rapamycin complex 1 (mTORC1) tightly regulates neonatal NSC self-renewal and differentiation, ultimately controlling neuron production and density. The mTORC1 downstream effector 4E-BP2 directs NSC differentiation by switching protein translation on and off. These findings suggest how aging might lead to NSC exhaustion through mTORC1 and identify 4E-BP2 as a possible target for preventing or rescuing abnormal brain development.