Insulin-like signaling (IIS) has both cell autonomous and non-autonomous functions. Direct targets have been identified which mediate cell-autonomous IIS functions, such as regulating cell growth and metabolism. In contrast, targets for non-autonomous IIS functions, such as C. elegans dauer morphogenesis, remain elusive. Here, we report the use of genomic and genetic approaches to identify targets non-autonomously regulated by C. elegans IIS. Transcriptional microarrays were used to identify target genes regulated non-autonomously by IIS in the intestine or in neurons. C. elegans IIS regulates expression of a number of stress response genes, which were differentially regulated by tissue-restricted IIS. In particular, expression of
sod-3, a MnSOD enzyme, was not regulated by tissue-restricted IIS on the microarrays, while expression of
hsp-16 genes was rescued back to wildtype by tissue restricted IIS. Two IIS targets regulated non-autonomously by
age-1 were
cat-4, encoding a component of the biopterin biosynthetic pathway, and cyp-35B1/dod-13, encoding a cytochrome P450. In
daf-2 mutants,
daf-16 was required for cyp-35B1 intestinal expression and
cat-4 seam cell expression. However,
cat-4 expression in seam cells could also be activated through
daf-16-independent mechanisms. Genetic and promoter analysis indicate that both cyp-35B1 and
cat-4 are direct DAF-16 targets. In addition,
cat-4 and cyp-35B1 expression was modified by
hsf-1, which directs
hsp-16 expression. Based on these findings, we propose a model in which DAF-16 and HSF-1 act collaboratively in the regulation of non-autonomous IIS target genes.