Identifying the transcriptional programs underlying neuronal phenotypes in young and aging C. elegans

The mature nervous system mediates a variety of biological processes that deteriorate as organisms age. Long-term memory and axonal regeneration are two such neuron-specific behaviors that exhibit age-dependent decline. Remarkably, we found that long-lived daf-2/insulin receptor mutants are protected from the age-dependent decay of both these phenotypes.

The transcription factor CREB mediates long-term memory in all organisms tested. CREB levels normally reduce with age and are correlated with the decline of long-term memory. We found that CREB levels are higher in daf-2 mutants, and correlate with their enhanced long-term memory. Since the full repertoire of CREB transcriptional targets required specifically for memory is not known in any system, we combined memory training with genome-wide transcriptional analysis of C. elegans CREB mutants using microarrays. This approach identified 757 significant CREB/memory-induced targets and confirmed the involvement of known memory genes from other organisms, but also suggested new mechanisms and novel components that may be conserved through mammals.

The insulin-signaling pathway has diverse tissue-specific functional outputs. To characterize the neuronal transcriptome of daf-2 mutants, we developed a method to isolate adult C. elegans cells that recapitulates the in vivo state. Using high-throughput RNA-sequencing, we have transcriptionally profiled adult neuronal tissue of daf-2 mutants, which have increased axonal regenerative capacity upon injury in older animals. We found that the transcription factor FKH-9, which is likely a direct transcriptional target of DAF-16/FOXO, is required for the extended regenerative ability of PLM mechanosensory axons in daf-2 animals. Ongoing experiments are examining the mechanisms by which FKH-9 mediates axonal regrowth post-injury.