mTORC1 targets the translational repressor 4E-BP2, but not S6 kinase 1/2, to regulate neural stem cell self-renewal in vivo

Nathaniel W Hartman; Tiffany V Lin; Longbo Zhang; Grace E Paquelet; David M Feliciano; Angélique Bordey

doi:10.1016/j.celrep.2013.09.017

mTORC1 targets the translational repressor 4E-BP2, but not S6 kinase 1/2, to regulate neural stem cell self-renewal in vivo

Cell Rep. 2013 Oct 31;5(2):433-44. doi: 10.1016/j.celrep.2013.09.017. Epub 2013 Oct 17.

Authors

Nathaniel W Hartman¹, Tiffany V Lin, Longbo Zhang, Grace E Paquelet, David M Feliciano, Angélique Bordey

Affiliation

¹ Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8082, USA.

PMID: 24139800
DOI: 10.1016/j.celrep.2013.09.017

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Carrier Proteins / metabolism
Cell Cycle Proteins
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
RNA Interference
RNA, Small Interfering / metabolism
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
Sirolimus / pharmacology
TOR Serine-Threonine Kinases / metabolism*

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
Cell Cycle Proteins
Eif4ebp1 protein, mouse
Eif4ebp2 protein, mouse
Eukaryotic Initiation Factors
Multiprotein Complexes
Neuropeptides
Phosphoproteins
RNA, Small Interfering
Ras Homolog Enriched in Brain Protein
Rheb protein, mouse
Mechanistic Target of Rapamycin Complex 1
Ribosomal Protein S6 Kinases, 90-kDa
Rps6ka1 protein, mouse
TOR Serine-Threonine Kinases
ribosomal protein S6 kinase, 90kDa, polypeptide 3
Monomeric GTP-Binding Proteins
Sirolimus