PMID- 28101526 OWN - NLM STAT- MEDLINE DCOM- 20171024 LR - 20211204 IS - 2373-2822 (Electronic) IS - 2373-2822 (Linking) VI - 3 IP - 6 DP - 2016 Nov-Dec TI - Rapamycin-Resistant mTOR Activity Is Required for Sensory Axon Regeneration Induced by a Conditioning Lesion. LID - 10.1523/ENEURO.0358-16.2016 [doi] LID - ENEURO.0358-16.2016 AB - 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. FAU - Chen, Weitao AU - Chen W AUID- ORCID: 0000-0003-3504-011X AD - 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. FAU - Lu, Na AU - Lu N AD - 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. FAU - Ding, Yue AU - Ding Y AD - 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. FAU - Wang, Yuan AU - Wang Y AUID- ORCID: 0000-0002-5977-2422 AD - 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. FAU - Chan, Leung Ting AU - Chan LT AD - 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. FAU - Wang, Xu AU - Wang X AD - 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. FAU - Gao, Xin AU - Gao X AD - 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. FAU - Jiang, Songshan AU - Jiang S AD - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou, 510006, China. FAU - Liu, Kai AU - Liu K AD - 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. LA - eng PT - Journal Article DEP - 20170113 PL - United States TA - eNeuro JT - eNeuro JID - 101647362 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Carrier Proteins) RN - 0 (Multiprotein Complexes) RN - 0 (Peripheral Nervous System Agents) RN - 0 (Rapamycin-Insensitive Companion of mTOR Protein) RN - 0 (Regulatory-Associated Protein of mTOR) RN - 0 (Rptor protein, mouse) RN - 0 (STAT3 Transcription Factor) RN - 0 (Stat3 protein, mouse) RN - 0 (rictor protein, mouse) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adaptor Proteins, Signal Transducing/genetics/*metabolism MH - Animals MH - Axons/drug effects/*metabolism/pathology MH - Carrier Proteins/genetics/*metabolism MH - Cells, Cultured MH - Female MH - Ganglia, Spinal/drug effects/*metabolism/pathology MH - Male MH - Mechanistic Target of Rapamycin Complex 1 MH - Mechanistic Target of Rapamycin Complex 2 MH - Mice, Transgenic MH - Multiprotein Complexes/metabolism MH - Nerve Regeneration/drug effects/*physiology MH - Peripheral Nervous System Agents/pharmacology MH - Rapamycin-Insensitive Companion of mTOR Protein MH - Regulatory-Associated Protein of mTOR MH - STAT3 Transcription Factor/metabolism MH - Sciatic Neuropathy/drug therapy/metabolism/pathology MH - Sensory Receptor Cells/drug effects/*metabolism/pathology MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC5234127 OTO - NOTNLM OT - Stat3 OT - axon regeneration OT - conditioning lesion OT - dorsal root ganglion OT - mTOR OT - spinal cord injury COIS- Authors report no conflict of interest. EDAT- 2017/01/20 06:00 MHDA- 2017/10/25 06:00 PMCR- 2017/01/13 CRDT- 2017/01/20 06:00 PHST- 2016/12/04 00:00 [received] PHST- 2016/12/12 00:00 [accepted] PHST- 2017/01/20 06:00 [entrez] PHST- 2017/01/20 06:00 [pubmed] PHST- 2017/10/25 06:00 [medline] PHST- 2017/01/13 00:00 [pmc-release] AID - eN-NWR-0358-16 [pii] AID - 10.1523/ENEURO.0358-16.2016 [doi] PST - epublish SO - eNeuro. 2017 Jan 13;3(6):ENEURO.0358-16.2016. doi: 10.1523/ENEURO.0358-16.2016. eCollection 2016 Nov-Dec.