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

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. Overall design: Bulk RNA-seq profiling of early adult wild type (N2) Caenorhabditis elegans. Individuals experienced 8 days of L1 arrest then were recovered on the indicated food source (RNAi treatment)