Insulin/IGF1 signaling inhibits age-dependent axon regeneration.
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.
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
Alexandra B
AB
Byrne
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
Trent
T
Walradt
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Kathryn E
KE
Gardner
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
Austin
A
Hubbert
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Valerie
V
Reinke
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: marc.hammarlund@yale.edu.
Marc
M
Hammarlund
D000375:Aging / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; C116661:DAF-18 protein, C elegans; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D007328:Insulin; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D049452:Green Fluorescent Proteins; D007334:Insulin-Like Growth Factor I; D017853:Phosphotransferases (Alcohol Group Acceptor); C472494:let-363 protein, C elegans; D051059:PTEN Phosphohydrolase; D020123:Sirolimus