Abstract
Insulin/IGF-I-like signaling (IIS) has both cell autonomous and non-autonomous functions. In some cases, targets through which IIS regulates cell-autonomous functions, such as cell growth and metabolism, have been identified. In contrast, targets for many non-autonomous IIS functions, such as C. elegans dauer morphogenesis, remain elusive. Here, we report the use of genomic and genetic approaches to identify potential non-autonomous targets of C. elegans IIS. First, we used transcriptional microarrays to identify target genes regulated non-autonomously by IIS in the intestine or in neurons. C. elegans IIS controls 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. One IIS target regulated non-autonomously by age-1 was cyp-35B1/dod-13, encoding a cytochrome P450. Genetic analysis of the cyp-35B1 promoter showed both DAF-16 and HSF-1 are direct regulators. Based on these findings, we propose that hsf-1 may participate in the pathways mediating non-autonomous activities of age-1 in C. elegans.
Highlights
Insulin/IGF-I-like signaling (IIS) is a highly conserved pathway for promoting growth under replete conditions
The extended lifespan of age-1(mg44) adults was rescued by age-1 expression in either tissue, CY262 more strongly rescued adult longevity than CY251, consistent with a critical role for intestinal daf-16 activity for extended lifespan [6]
Expression of wildtype age-1 within neurons or intestinal cells rescues dauer arrest and lifespan phenotypes of age-1(mg44) animals [7,8]. This evidence led to a working model whereby age-1 activity within signaling tissues regulates an endocrine output that, in turn, can direct dauer morphogenesis and aging in target tissues [8]
Summary
Insulin/IGF-I-like signaling (IIS) is a highly conserved pathway for promoting growth under replete conditions. Growth control is cell-autonomously regulated by IIS to determine cell and organ size in the affected tissue [1,2] In addition to this well-conserved cellautonomous function, IIS can have non-autonomous effects on other parts of the body. Tissue-restricted IIS could confer these non-autonomous effects either through endocrine outputs, or non-through pleiotropic phenotypes resulting from tissue dysfunction due to inadequate growth. These findings raise new challenges for identifying the downstream pathways mediating non-autonomous effects of IIS [10]
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