Abstract
The ability of injured axons to regenerate declines with age, yet the mechanisms that regulate axon regeneration in response to age are not known. Here we show that axon regeneration in aging C. elegans motor neurons is inhibited by the conserved insulin/IGF1 receptor DAF-2. DAF-2's function in regeneration is mediated by intrinsic neuronal activity of the forkhead transcription factor DAF-16/FOXO. DAF-16 regulates regeneration independently of lifespan, indicating that neuronal aging is an intrinsic, neuron-specific, and genetically regulated process. In addition, we found that DAF-18/PTEN inhibits regeneration independently of age and FOXO signaling via the TOR pathway. Finally, DLK-1, a conserved regulator of regeneration, is downregulated by insulin/IGF1 signaling, bound by DAF-16 in neurons, and required for both DAF-16- and DAF-18-mediated regeneration. Together, our data establish that insulin signaling specifically inhibits regeneration in aging adult neurons and that this mechanism is independent of PTEN and TOR.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / physiology*
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Animals
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Animals, Genetically Modified
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Caenorhabditis elegans
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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Disease Models, Animal
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Forkhead Transcription Factors
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Gene Expression Regulation / genetics
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Green Fluorescent Proteins / genetics
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Humans
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Immunosuppressive Agents / pharmacology
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Insulin / metabolism*
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism*
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Nerve Degeneration / genetics
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Nerve Degeneration / pathology
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Nerve Degeneration / physiopathology*
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Nerve Regeneration / genetics
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Nerve Regeneration / physiology*
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Sirolimus / pharmacology
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Caenorhabditis elegans Proteins
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DAF-18 protein, C elegans
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Forkhead Transcription Factors
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Immunosuppressive Agents
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Insulin
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Transcription Factors
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daf-16 protein, C elegans
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Green Fluorescent Proteins
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Insulin-Like Growth Factor I
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Phosphotransferases (Alcohol Group Acceptor)
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let-363 protein, C elegans
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PTEN Phosphohydrolase
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Sirolimus