Mammalian target of Rapamycin’s distinct roles and effectiveness in promoting compensatory axonal sprouting in the injured CNS

Do Hun Lee, Xueting Luo, Benjamin J. Yungher, Eric Bray, Jae Lee, Kevin Park

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Mammalian target of rapamycin (mTOR) functions as a master sensor of nutrients and energy, and controls protein translation and cell growth. Deletion of phosphatase and tensin homolog (PTEN) in adult CNS neurons promotes regeneration of injured axons in an mTOR-dependent manner. However, others have demonstrated mTOR-independent axon regeneration in different cell types, raising the question of how broadly mTOR regulates axonal regrowth across different systems. Here we define the role of mTOR in promoting collateral sprouting of spared axons, a key axonal remodeling mechanism by which functions are recovered after CNS injury. Using pharmacological inhibition, we demonstrate that mTOR is dispensable for the robust spontaneous sprouting of corticospinal tract axons seen after pyramidotomy in postnatal mice. In contrast, moderate spontaneous axonal sprouting and induced-sprouting seen under different conditions in young adult mice (i.e., PTEN deletion or degradation of chondroitin proteoglycans; CSPGs) are both reduced upon mTOR inhibition. In addition, to further determine the potency of mTOR in promoting sprouting responses, we coinactivate PTEN and CSPGs, and demonstrate that this combination leads to an additive increase in axonal sprouting compared with single treatments. Our findings reveal a developmental switch in mTOR dependency for inducing axonal sprouting, and indicate that PTEN deletion in adult neurons neither recapitulates the regrowth program of postnatal animals, nor is sufficient to completely overcome an inhibitory environment. Accordingly, exploiting mTOR levels by targeting PTEN combined with CSPG degradation represents a promising strategy to promote extensive axonal plasticity in adult mammals.

Original languageEnglish
Pages (from-to)15347-15355
Number of pages9
JournalJournal of Neuroscience
Volume34
Issue number46
DOIs
StatePublished - Jan 1 2014

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Sirolimus
Phosphoric Monoester Hydrolases
Axons
Regeneration
Chondroitin
Neurons
Pyramidal Tracts
Protein Biosynthesis
Proteoglycans
Young Adult
Mammals
Tensins
Pharmacology
Food
Wounds and Injuries

Keywords

  • Axon growth
  • Axon regeneration
  • Axon sprouting
  • MTOR
  • PTEN
  • Pyramidotomy

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mammalian target of Rapamycin’s distinct roles and effectiveness in promoting compensatory axonal sprouting in the injured CNS. / Lee, Do Hun; Luo, Xueting; Yungher, Benjamin J.; Bray, Eric; Lee, Jae; Park, Kevin.

In: Journal of Neuroscience, Vol. 34, No. 46, 01.01.2014, p. 15347-15355.

Research output: Contribution to journalArticle

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