Early life starvation and Hedgehog-related signaling activate innate immunity downstream of daf-18/PTEN and lin-35/Rb causing developmental abnormalities in adult C. elegans

ABSTRACT Early life experiences such as malnutrition can affect development and adult disease risk, but the molecular basis of such protracted effects is poorly understood. In the nematode C. elegans, extended starvation during the first larval stage causes the development of germline tumors and other abnormalities in the adult gonad, limiting reproductive success. Insulin/IGF signaling (IIS) acts through WNT signaling and lipid metabolism to promote starvation-induced gonad abnormalities, but IIS-independent modifiers have not been identified. We show that the tumor suppressors daf-18/PTEN and lin-35/Rb act independently of IIS to suppress starvation-induced abnormalities. We found that lin-35/Rb antagonizes activity of the Hedgehog (Hh) signaling homologs ptr-23/PTCH-related, wrt-1/Hh-like, wrt-10/Hh-like, and tra-1/GLI, which promote starvation-induced abnormalities. These Hh-related genes transcriptionally activate several genes associated with innate immunity in adults, which also promote starvation-induced gonad abnormalities. Surprisingly, we found that in addition to causing developmental abnormalities, early-life starvation induces an innate immune response later in life, leading to increased resistance to multiple bacterial pathogens. This work identifies a critical tumor-suppressor function of daf-18/PTEN independent of IIS, and it defines a regulatory network, including lin-35/Rb, Hh-related signaling, and the innate immunity pathway, that affects development of tumors and other developmental abnormalities resulting from early life starvation. By revealing that early-life starvation increases immunity later in life, this work suggests a fitness tradeoff between pathogen resistance and developmental robustness. AUTHOR SUMMARY Early life malnutrition can promote adult disease, including the risk of developing cancer. We previously found that the roundworm Caenorhabditis elegans develops tumors in well-fed adults following early life starvation, reflecting a breakdown of developmental fidelity. This powerful model system provides an excellent opportunity to identify molecular mechanisms that mediate the effects of early life starvation on development and adult physiology. Reducing insulin-like/IGF signaling during recovery from starvation suppresses tumor formation, but other regulatory pathways have not been identified. Here we show that a pair of important tumor suppressor genes, daf-18/PTEN and lin-35/Rb, function independently of insulin/IGF signaling to suppress starvation-induced abnormalities. lin-35/Rb represses the activity of genes involved in Hedgehog signaling, a cancer-causing pathway, which promote starvation-induced abnormalities. Hedgehog signaling activates an immune response, which, surprisingly, contributes to formation of tumors but renders adult worms resistant to pathogenic bacteria. Adult activation of this immune response by early life starvation suggests an evolutionary fitness tradeoff between pathogen resistance and developmental fidelity. Competing Interest Statement The authors have declared no competing interest.