Mammalian target of rapamycin's distinct roles and effectiveness in promoting compensatory axonal sprouting in the injured CNS.
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.
Miami Project to Cure Paralysis and Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida 33136.
Do-Hun
DH
Lee
Miami Project to Cure Paralysis and Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida 33136.
Xueting
X
Luo
Miami Project to Cure Paralysis and Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida 33136.
Benjamin J
http://orcid.org/0000-0002-0499-2516
BJ
Yungher
Miami Project to Cure Paralysis and Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida 33136.
Eric
E
Bray
Miami Project to Cure Paralysis and Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida 33136 kpark@med.miami.edu JLee22@med.miami.edu.
Jae K
JK
Lee
Miami Project to Cure Paralysis and Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida 33136 kpark@med.miami.edu JLee22@med.miami.edu.
Kevin K
KK
Park
D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D001369:Axons / Q000502:physiology*; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D011508:Chondroitin Sulfate Proteoglycans / Q000037:antagonists & inhibitors / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D011712:Pyramidal Tracts / Q000187:drug effects / Q000293:injuries / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D011508:Chondroitin Sulfate Proteoglycans; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D019765:Chondroitin ABC Lyase; D020123:Sirolimus
PTEN; axon growth; axon regeneration; axon sprouting; mTOR; pyramidotomy