The ability of axons to regenerate depends on the age of the neuron in all model organisms tested, including humans. Young axons (including CNS axons) regenerate efficiently, whereas old axons either do not regrow at all, or make errors while navigating to their target (Verdu et al., 2000; Wu et al., 2007). Insulin/IGF-1 signaling (IIS) is a critical regulator of the most important biological decisions, from rates of growth, development, and metabolism, to reproduction and longevity. Long-lived daf-2 insulin/IGF1 receptor mutants exhibit enhanced axonal regenerative capacity in older GABAergic motor neurons and PLM mechanosensory neurons (Byrne et al., 2014, Lakhina et al., submitted). This occurs through the activity of the DAF-16/FOXO transcription factor, which regulates regeneration independent of lifespan, and in a neuron-specific manner (Byrne et al., 2014). While the global, whole-worm targets of DAF-16 were identified in C. elegans using whole-worm transcriptional analyses more than a decade ago (Murphy et al., 2003; Lee et al., 2003; McElwee et al., 2003), neuron-specific DAF-16 targets remain elusive. We have selectively isolated adult C. elegans neurons and performed transcriptional profiling. The neuron-enriched set includes synaptic machinery, channels, neurotransmitters, and signaling components, as well as >700 previously uncharacterized genes. Comparison of the embryonic and larval neuronal transcriptomes with this new adult neuronal transcriptome revealed a shift in functional categories from developmental processes to neuronal function and behavior. We next used this approach to directly identify IIS/FOXO targets from isolated daf-2 and daf-16;daf-2 neurons. IIS/FOXO neuron-specific targets are distinct from canonical IIS/FOXO-regulated longevity and metabolism targets. We also selectively sequenced six mechanosensory neurons and identified 63 mechanosensory neuron-specific DAF-16 targets. We discovered that a transcription factor that is upregulated in daf-2 neurons is almost entirely responsible for daf-2’s enhanced ability to regenerate PLM mechanosensory axons with age. These studies identify a set of adult neuronal FOXO targets and potentially a new set of candidate age-dependent axonal regeneration factors.
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