title: Rapamycin-Resistant mTOR Activity Is Required for Sensory Axon Regeneration Induced by a Conditioning Lesion.
abstract: Neuronal mammalian target of rapamycin (mTOR) activity is a critical determinant of the intrinsic regenerative ability of mature neurons in the adult central nervous system (CNS). However, whether its action also applies to peripheral nervous system (PNS) neurons after injury remains elusive. To address this issue unambiguously, we used genetic approaches to determine the role of mTOR signaling in sensory axon regeneration in mice. We showed that deleting mTOR in dorsal root ganglion (DRG) neurons suppressed the axon regeneration induced by conditioning lesions. To establish whether the impact of mTOR on axon regeneration results from functions of mTOR complex 1 (mTORC1) or 2 (mTORC2), two distinct kinase complexes, we ablated either Raptor or Rictor in DRG neurons. We found that suppressing mTORC1 signaling dramatically decreased the conditioning lesion effect. In addition, an injury to the peripheral branch boosts mTOR activity in DRG neurons that cannot be completely inhibited by rapamycin, a widely used mTOR-specific inhibitor. Unexpectedly, examining several conditioning lesion-induced pro-regenerative pathways revealed that Raptor deletion but not rapamycin suppressed Stat3 activity in neurons. Therefore, our results demonstrate that crosstalk between mTOR and Stat3 signaling mediates the conditioning lesion effect and provide genetic evidence that rapamycin-resistant mTOR activity contributes to the intrinsic axon growth capacity in adult sensory neurons after injury.
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Weitao
authors.identifier: 0000-0003-3504-011X
authors.initials: W
authors.lastname: Chen
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Yuan
authors.identifier: 0000-0002-5977-2422
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Leung Ting
authors.initials: LT
authors.lastname: Chan
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou, 510006, China.
authors.forename: Songshan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D018373:Peripheral Nervous System Agents / Q000494:pharmacology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D050796:STAT3 Transcription Factor / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D018373:Peripheral Nervous System Agents; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C525637:rictor protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Stat3; axon regeneration; conditioning lesion; dorsal root ganglion; mTOR; spinal cord injury