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Neuron. 2014 Feb 5;81(3):561-73. doi: 10.1016/j.neuron.2013.11.019. Epub 2014 Jan 16.

Insulin/IGF1 signaling inhibits age-dependent axon regeneration.

Author information

1
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.
2
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
3
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.

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.

PMID:
24440228
PMCID:
PMC3924874
DOI:
10.1016/j.neuron.2013.11.019
[Indexed for MEDLINE]
Free PMC Article

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