Developmental responses to nutrient stress reflect systems-level regulation -- the entire animal and its progeny can be affected. But how developmental physiology is coordinated across the animal and over generations is not well understood. The long-term goal of this project is to understand how nutrient availability governs development. C. elegans has evolved to survive feast and famine, and development can be stopped, started and otherwise manipulated by controlling food supply. Worms also enable genetic analysis at the cellular and organismal levels, and transgenerational studies are facilitated by short generation time. Furthermore, lack of DNA methylation suggests alternative, less understood epigenetic mechanisms. When larvae hatch in the absence of food they reversibly arrest development (`L1 arrest'). Insulin-like signaling regulates L1 arrest, and daf-16/FOXO mutants are arrest-defective. Preliminary results show that daf-16/FOXO regulates L1 arrest cell- nonautonomously, and they identify two conserved signaling pathways operating downstream of it. These pathways promote development in fed larvae, but daf-16/FOXO represses them during starvation. Insulin-like signaling also mediates effects of caloric restriction on maternal provisioning, affecting progeny size and growth during starvation recovery. Starvation during L1 arrest also causes increased starvation survival and heat resistance as well as altered gene expression for up to three generations. These exciting preliminary results suggest that the worm can be used to model long-term effects of nutrient stress on disease risk, including both maternal and epigenetic effects. The central hypothesis of this proposal is that nutrient stress affects developmental physiology systemically, maternally and transgenerationally. The objectives of this proposal are to identify signaling pathways and gene regulatory mechanisms that mediate such effects. The rationale is to use an ideally suited model system to determine how developmental responses to nutrient stress are coordinated across the animal and its lifecycle. The central hypothesis is supported by strong preliminary data as well as the literature. It will be tested with the following three aims: 1) identify daf-16/FOXO-regulated signals mediating systemic control of developmental arrest, 2) identify mechanisms for maternal effects of caloric restriction on size and starvation recovery and 3) identify epigenetic mechanisms and effector genes for inheritance of stress resistance. Genetic, genomic, cell biological and biochemical analyses will be used to complete these aims. Primarily existing strains and phenotypic assays presented in preliminary studies will be used. This proposal is innovative for developing a simple organismal model of systemic and long-term effects of nutrient stress on development and disease risk. This research will be significant because it will fill critical gaps in understanding of how nutrient stress affects cellular behavior, maternal provisioning and inheritance of disease risk. The deeply conserved role of insulin-like signaling and other energy homeostasis pathways suggests that the mechanisms discovered will be conserved.
The proposed research is relevant to public health given the paramount importance of nutrition on health and disease. Disruption of pathways mediating nutritional control of development causes cancer, and malnutrition during early development is linked to increased risk of cancer, diabetes and cardiovascular disease. This work will increase fundamental understanding of how nutrient availability influences development and disease, sug- gesting novel diagnostics, therapeutic interventions and preventive strategies to reduce public health burden.
