Mammalian Target of Rapamycin (mTOR) Activation Increases Axonal Growth Capacity of Injured Peripheral Nerves
Unlike neurons in the central nervous system (CNS), injured neurons in the peripheral nervous system (PNS) can regenerate their axons and reinnervate their targets. However, functional recovery in the PNS often remains suboptimal, especially in cases of severe damage. The lack of regenerative abilit...
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creator | Abe, Namiko Borson, Steven H. Gambello, Michael J. Wang, Fan Cavalli, Valeria |
description | Unlike neurons in the central nervous system (CNS), injured neurons in the peripheral nervous system (PNS) can regenerate their axons and reinnervate their targets. However, functional recovery in the PNS often remains suboptimal, especially in cases of severe damage. The lack of regenerative ability of CNS neurons has been linked to down-regulation of the mTOR (mammalian target of rapamycin) pathway. We report here that PNS dorsal root ganglial neurons (DRGs) activate mTOR following damage and that this activity enhances axonal growth capacity. Furthermore, genetic up-regulation of mTOR activity by deletion of tuberous sclerosis complex 2 (TSC2) in DRGs is sufficient to enhance axonal growth capacity in vitro and in vivo. We further show that mTOR activity is linked to the expression of GAP-43, a crucial component of axonal outgrowth. However, although TSC2 deletion in DRGs facilitates axonal regrowth, it leads to defects in target innervation. Thus, whereas manipulation of mTOR activity could provide new strategies to stimulate nerve regeneration in the PNS, fine control of mTOR activity is required for proper target innervation. |
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However, functional recovery in the PNS often remains suboptimal, especially in cases of severe damage. The lack of regenerative ability of CNS neurons has been linked to down-regulation of the mTOR (mammalian target of rapamycin) pathway. We report here that PNS dorsal root ganglial neurons (DRGs) activate mTOR following damage and that this activity enhances axonal growth capacity. Furthermore, genetic up-regulation of mTOR activity by deletion of tuberous sclerosis complex 2 (TSC2) in DRGs is sufficient to enhance axonal growth capacity in vitro and in vivo. We further show that mTOR activity is linked to the expression of GAP-43, a crucial component of axonal outgrowth. However, although TSC2 deletion in DRGs facilitates axonal regrowth, it leads to defects in target innervation. Thus, whereas manipulation of mTOR activity could provide new strategies to stimulate nerve regeneration in the PNS, fine control of mTOR activity is required for proper target innervation.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M110.125336</identifier><identifier>PMID: 20615870</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Axon ; Axon Regeneration ; Axons - metabolism ; Developmental Biology ; DRG Neuron ; Female ; Ganglia, Spinal - metabolism ; Ganglia, Spinal - pathology ; GAP-43 Protein - metabolism ; Gap43 ; Gene Deletion ; Gene Expression Regulation ; Humans ; Intracellular Signaling Peptides and Proteins - metabolism ; Mice ; mTOR ; Neurobiology ; Neurodevelopment ; Peripheral Nerve Injuries ; Peripheral Nerves - metabolism ; Peripheral Nerves - pathology ; Peripheral Nerves - physiopathology ; Protein-Serine-Threonine Kinases - metabolism ; Recovery of Function ; Regeneration ; TOR Complex (TORC) ; TOR Serine-Threonine Kinases ; Translation Regulation ; TSC2 ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins - deficiency ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism</subject><ispartof>The Journal of biological chemistry, 2010-09, Vol.285 (36), p.28034-28043</ispartof><rights>2010 © 2010 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2010 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c578t-8215da6d042be85eca49d340e3251e697497f692b3afeee5c793562432d4e8033</citedby><cites>FETCH-LOGICAL-c578t-8215da6d042be85eca49d340e3251e697497f692b3afeee5c793562432d4e8033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934668/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934668/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20615870$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Abe, Namiko</creatorcontrib><creatorcontrib>Borson, Steven H.</creatorcontrib><creatorcontrib>Gambello, Michael J.</creatorcontrib><creatorcontrib>Wang, Fan</creatorcontrib><creatorcontrib>Cavalli, Valeria</creatorcontrib><title>Mammalian Target of Rapamycin (mTOR) Activation Increases Axonal Growth Capacity of Injured Peripheral Nerves</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Unlike neurons in the central nervous system (CNS), injured neurons in the peripheral nervous system (PNS) can regenerate their axons and reinnervate their targets. However, functional recovery in the PNS often remains suboptimal, especially in cases of severe damage. The lack of regenerative ability of CNS neurons has been linked to down-regulation of the mTOR (mammalian target of rapamycin) pathway. We report here that PNS dorsal root ganglial neurons (DRGs) activate mTOR following damage and that this activity enhances axonal growth capacity. Furthermore, genetic up-regulation of mTOR activity by deletion of tuberous sclerosis complex 2 (TSC2) in DRGs is sufficient to enhance axonal growth capacity in vitro and in vivo. We further show that mTOR activity is linked to the expression of GAP-43, a crucial component of axonal outgrowth. However, although TSC2 deletion in DRGs facilitates axonal regrowth, it leads to defects in target innervation. Thus, whereas manipulation of mTOR activity could provide new strategies to stimulate nerve regeneration in the PNS, fine control of mTOR activity is required for proper target innervation.</description><subject>Animals</subject><subject>Axon</subject><subject>Axon Regeneration</subject><subject>Axons - metabolism</subject><subject>Developmental Biology</subject><subject>DRG Neuron</subject><subject>Female</subject><subject>Ganglia, Spinal - metabolism</subject><subject>Ganglia, Spinal - pathology</subject><subject>GAP-43 Protein - metabolism</subject><subject>Gap43</subject><subject>Gene Deletion</subject><subject>Gene Expression Regulation</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Mice</subject><subject>mTOR</subject><subject>Neurobiology</subject><subject>Neurodevelopment</subject><subject>Peripheral Nerve Injuries</subject><subject>Peripheral Nerves - metabolism</subject><subject>Peripheral Nerves - pathology</subject><subject>Peripheral Nerves - physiopathology</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Recovery of Function</subject><subject>Regeneration</subject><subject>TOR Complex (TORC)</subject><subject>TOR Serine-Threonine Kinases</subject><subject>Translation Regulation</subject><subject>TSC2</subject><subject>Tuberous Sclerosis Complex 2 Protein</subject><subject>Tumor Suppressor Proteins - deficiency</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1vEzEQxVcIRNPCmRv4Bhy29eeufakURVAitRSVVOJmOd7ZxNGuHexNSv57HG2p4IAvI2t-781oXlG8Ific4JpfbJb2_IYcf1QwVj0rJgRLVjJBfjwvJhhTUioq5ElxmtIG58cVeVmcUFwRIWs8Kfob0_emc8ajhYkrGFBo0Z3Zmv5gnUcf-sXt3Uc0tYPbm8EFj-beRjAJEpr-Ct506CqGh2GNZllj3XA46ud-s4vQoG8Q3XYNMVNfIe4hvSpetKZL8PqxnhX3nz8tZl_K69ur-Wx6XVpRy6GUlIjGVA3mdAlSgDVcNYxjYFQQqFTNVd1Wii6ZaQFA2FoxUVHOaMNBYsbOisvRd7tb9tBY8ENeQm-j60086GCc_rfj3Vqvwl5TxXhVyWzw_tEghp87SIPuXbLQdcZD2CUta0oox0Rk8mIkbQwpRWifphCsjxnpnJE-ZqTHjLLi7d_LPfF_QsnAuxFoTdBmFV3S998pJgwTKWmteCbUSEA-4t5B1Mk68BYaF8EOugnuv-N_Az0Qqpk</recordid><startdate>20100903</startdate><enddate>20100903</enddate><creator>Abe, Namiko</creator><creator>Borson, Steven H.</creator><creator>Gambello, Michael J.</creator><creator>Wang, Fan</creator><creator>Cavalli, Valeria</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>5PM</scope></search><sort><creationdate>20100903</creationdate><title>Mammalian Target of Rapamycin (mTOR) Activation Increases Axonal Growth Capacity of Injured Peripheral Nerves</title><author>Abe, Namiko ; Borson, Steven H. ; Gambello, Michael J. ; Wang, Fan ; Cavalli, Valeria</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c578t-8215da6d042be85eca49d340e3251e697497f692b3afeee5c793562432d4e8033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Axon</topic><topic>Axon Regeneration</topic><topic>Axons - metabolism</topic><topic>Developmental Biology</topic><topic>DRG Neuron</topic><topic>Female</topic><topic>Ganglia, Spinal - metabolism</topic><topic>Ganglia, Spinal - pathology</topic><topic>GAP-43 Protein - metabolism</topic><topic>Gap43</topic><topic>Gene Deletion</topic><topic>Gene Expression Regulation</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Mice</topic><topic>mTOR</topic><topic>Neurobiology</topic><topic>Neurodevelopment</topic><topic>Peripheral Nerve Injuries</topic><topic>Peripheral Nerves - metabolism</topic><topic>Peripheral Nerves - pathology</topic><topic>Peripheral Nerves - physiopathology</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Recovery of Function</topic><topic>Regeneration</topic><topic>TOR Complex (TORC)</topic><topic>TOR Serine-Threonine Kinases</topic><topic>Translation Regulation</topic><topic>TSC2</topic><topic>Tuberous Sclerosis Complex 2 Protein</topic><topic>Tumor Suppressor Proteins - deficiency</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Abe, Namiko</creatorcontrib><creatorcontrib>Borson, Steven H.</creatorcontrib><creatorcontrib>Gambello, Michael J.</creatorcontrib><creatorcontrib>Wang, Fan</creatorcontrib><creatorcontrib>Cavalli, Valeria</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Abe, Namiko</au><au>Borson, Steven H.</au><au>Gambello, Michael J.</au><au>Wang, Fan</au><au>Cavalli, Valeria</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mammalian Target of Rapamycin (mTOR) Activation Increases Axonal Growth Capacity of Injured Peripheral Nerves</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2010-09-03</date><risdate>2010</risdate><volume>285</volume><issue>36</issue><spage>28034</spage><epage>28043</epage><pages>28034-28043</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Unlike neurons in the central nervous system (CNS), injured neurons in the peripheral nervous system (PNS) can regenerate their axons and reinnervate their targets. However, functional recovery in the PNS often remains suboptimal, especially in cases of severe damage. The lack of regenerative ability of CNS neurons has been linked to down-regulation of the mTOR (mammalian target of rapamycin) pathway. We report here that PNS dorsal root ganglial neurons (DRGs) activate mTOR following damage and that this activity enhances axonal growth capacity. Furthermore, genetic up-regulation of mTOR activity by deletion of tuberous sclerosis complex 2 (TSC2) in DRGs is sufficient to enhance axonal growth capacity in vitro and in vivo. We further show that mTOR activity is linked to the expression of GAP-43, a crucial component of axonal outgrowth. However, although TSC2 deletion in DRGs facilitates axonal regrowth, it leads to defects in target innervation. 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subjects | Animals Axon Axon Regeneration Axons - metabolism Developmental Biology DRG Neuron Female Ganglia, Spinal - metabolism Ganglia, Spinal - pathology GAP-43 Protein - metabolism Gap43 Gene Deletion Gene Expression Regulation Humans Intracellular Signaling Peptides and Proteins - metabolism Mice mTOR Neurobiology Neurodevelopment Peripheral Nerve Injuries Peripheral Nerves - metabolism Peripheral Nerves - pathology Peripheral Nerves - physiopathology Protein-Serine-Threonine Kinases - metabolism Recovery of Function Regeneration TOR Complex (TORC) TOR Serine-Threonine Kinases Translation Regulation TSC2 Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins - deficiency Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism |
title | Mammalian Target of Rapamycin (mTOR) Activation Increases Axonal Growth Capacity of Injured Peripheral Nerves |
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