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.

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
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • PTEN Phosphohydrolase
  • Pten protein, mouse