The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators

The FOXO transcription factor, DAF-16, is required for the long-life phenotype of daf-2 mutant nematode worms; here the authors find that daf-2 mutant worms maintain neuronal functions and behaviours with age by using a set of transcriptional targets that are distinct from previously identified canonical FOXO/DAF-16-regulated targets. Caenorhabditis elegans roundworms with a daf-2 mutation, making them defective in insulin/IGF-1 signalling, not only live longer, they also have an improved neuronal phenotype at old age, including better short- and long-term memory and better capacity to regenerate neurons. The FOXO transcription factor, DAF-16, is required for these effects. These authors describe the target genes that regulate this beneficial neuronal phenotype later in life. They find that daf-2 worms maintain neuronal functions and behaviours with age by using a set of transcriptional targets that are distinct from previously identified canonical FOXO/DAF-16-regulated targets. Insulin/insulin-like growth factor signalling (IIS) is a critical regulator of an organism’s most important biological decisions from growth, development, and metabolism to reproduction and longevity. It primarily does so through the activity of the DAF-16 transcription factor (forkhead box O (FOXO) homologue), whose global targets were identified in Caenorhabditis elegans using whole-worm transcriptional analyses more than a decade ago1. IIS and FOXO also regulate important neuronal and adult behavioural phenotypes, such as the maintenance of memory2 and axon regeneration3 with age, in both mammals4 and C. elegans, but the neuron-specific IIS/FOXO targets that regulate these functions are still unknown. By isolating adult C. elegans neurons for transcriptional profiling, we identified both the wild-type and IIS/FOXO mutant adult neuronal transcriptomes for the first time. IIS/FOXO neuron-specific targets are distinct from canonical IIS/FOXO-regulated longevity and metabolism targets, and are required for extended memory in IIS daf-2 mutants. The activity of the forkhead transcription factor FKH-9 in neurons is required for the ability of daf-2 mutants to regenerate axons with age, and its activity in non-neuronal tissues is required for the long lifespan of daf-2 mutants. Together, neuron-specific and canonical IIS/FOXO-regulated targets enable the coordinated extension of neuronal activities, metabolism, and longevity under low-insulin signalling conditions.