The mTORC1 effectors S6K1 and 4E-BP play different roles in CNS axon regeneration

Liu Yang; Linqing Miao; Feisi Liang; Haoliang Huang; Xiuyin Teng; Shaohua Li; Jaloliddin Nuriddinov; Michael E Selzer; Yang Hu

doi:10.1038/ncomms6416

The mTORC1 effectors S6K1 and 4E-BP play different roles in CNS axon regeneration

Nat Commun. 2014 Nov 10:5:5416. doi: 10.1038/ncomms6416.

Authors

Liu Yang¹, Linqing Miao¹, Feisi Liang¹, Haoliang Huang¹, Xiuyin Teng¹, Shaohua Li², Jaloliddin Nuriddinov³, Michael E Selzer⁴, Yang Hu¹

Affiliations

¹ Shriners Hospitals Pediatric Research Center (Center for Neural Repair and Rehabilitation), Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
² 1] Shriners Hospitals Pediatric Research Center (Center for Neural Repair and Rehabilitation), Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA [2] Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
³ Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
⁴ 1] Shriners Hospitals Pediatric Research Center (Center for Neural Repair and Rehabilitation), Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA [2] Department of Neurology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.

Abstract

Using mouse optic nerve (ON) crush as a CNS injury model, we and others have found that activation of the mammalian target of rapamycin complex 1 (mTORC1) in mature retinal ganglion cells by deletion of the negative regulators, phosphatase and tensin homologue (PTEN), and tuberous sclerosis 1 promotes ON regeneration. mTORC1 activation inhibits eukaryotic translation initiation factor 4E-binding protein (4E-BP) and activates ribosomal protein S6 kinase 1 (S6K1), both of which stimulate translation. We reasoned that mTORC1's regeneration-promoting effects might be separable from its deleterious effects by differential manipulation of its downstream effectors. Here we show that S6K1 activation, but not 4E-BP inhibition, is sufficient to promote axon regeneration. However, inhibition of 4E-BP is required for PTEN deletion-induced axon regeneration. Both activation and inhibition of S6K1 decrease the effect of PTEN deletion on axon regeneration, implicating a dual role of S6K1 in regulating axon growth.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Axons / physiology*
Carrier Proteins / physiology*
Cell Cycle Proteins
Cell Survival / physiology
Central Nervous System / cytology
Central Nervous System / physiology*
Eukaryotic Initiation Factors
Male
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Animal
Multiprotein Complexes / physiology*
Nerve Regeneration / physiology*
Optic Nerve Injuries / physiopathology
PTEN Phosphohydrolase / deficiency
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / physiology
Phosphoproteins / physiology*
Retinal Ganglion Cells / cytology
Retinal Ganglion Cells / physiology
Ribosomal Protein S6 Kinases, 90-kDa / physiology*
Signal Transduction / physiology
TOR Serine-Threonine Kinases / physiology*

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
Cell Cycle Proteins
Eif4ebp1 protein, mouse
Eukaryotic Initiation Factors
Multiprotein Complexes
Phosphoproteins
Mechanistic Target of Rapamycin Complex 1
Ribosomal Protein S6 Kinases, 90-kDa
Rps6ka1 protein, mouse
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase
Pten protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding