Transcriptome- and phenotype-based epistasis analysis in <i>Caenorhabditis elegans</i> reveals <i>daf-16/FoxO</i> -dependent and independent effects of <i>daf-2/InsR</i> in L1 starvation and recovery

Reduced insulin/IGF signaling (IIS) in Caenorhabditis elegans increases starvation resistance in a daf-16/FoxO-dependent fashion, but it is unclear whether the effects of reduced IIS are entirely dependent on daf-16/FoxO. We used RNA sequencing and phenotypic analysis of L1 starvation resistance to assess epistasis between daf-2/InsR and daf-16/FoxO. We identified 4,653 putative DAF-16/FoxO targets, many of which had not been previously identified, providing a valuable reference data set. Differential gene expression and increased survival caused by disruption of daf-2/InsR during starvation are daf-16-dependent. The effect of daf-2/InsR on growth following starvation is largely but not entirely daf-16-dependent. Notably, daf-16 is dispensable for reproduction following extended starvation, and daf-2 loss preserves reproductive success independent of daf-16. These results show that the effects of reduced IIS during L1 starvation are daf-16/FoxO-dependent but that IIS engages 1 or more additional effectors to buffer larval growth and especially reproduction from persistent effects of early life starvation.