Nutritional Control of Nematode Development

Duke University, Durham NC

Investigators

Abstract

SUMMARY Nutrient-responsive pathways govern gene expression and metabolism to adapt to starvation, and their dysregulation causes cancer, diabetes, and aging. The Baugh lab uses C. elegans to investigate how animals maintain developmental homeostasis despite fluctuations in nutrient availability. C. elegans is a premier animal model to study starvation responses, both acute and long-term. Worms reversibly arrest development in the first larval stage when they hatch without food (L1 arrest). The Baugh lab’s foundational work has shown that L1 arrest is a powerful model for cancer and aging, pathological effects of early life starvation on adults, and multigenerational plasticity. They discovered that insulin/IGF signaling (IIS) and daf-16/FoxO are critical regulators of L1 arrest, that RNA Pol II is poised at growth genes during starvation, that early life starvation causes adults to develop tumors, and inter- and transgenerational effects of starvation. Current work is focused on starvation resistance mechanisms, nutritional control of gene expression, long-term consequences of early life starvation, and maternal effects of diet and IIS on progeny. Despite substantial progress, significant knowledge gaps remain. Though well studied, the role of tumor suppressors daf-18/PTEN and lin-35/Rb in promoting starvation resistance is poorly understood. The IIS/PI3K-independent function of DAF-18 is uncharacterized, and LIN-35 effector mechanisms are unknown. Additional genes that support starvation resistance remain to be identified. The transcriptional response to starvation has been well characterized, but mechanisms responsible for tissue-specific responses have not been identified. The lab implicated IIS, lipid synthesis, Wnt, and Hedgehog-related signaling in development of starvation-induced tumors, but how these pathways interact is unclear. The lab discovered that daf-16 and mpk-1/MAPK regulate vitellogenin lipoprotein oocyte provisioning, but it is unclear how soma-to-germline trafficking of lipids is regulated. The long-term goal of this project is to elucidate the signaling and gene regulatory mechanisms that enable worms to adapt to fluctuations in nutrient availability as a model for understanding regulation of growth and quiescence in humans. The central hypothesis is that a conserved network of tumor suppressors governs the starvation response. The objective of this proposal is to close gaps in our understanding of this network by identifying novel components, regulatory interactions, and effector mechanisms. Goals include identification of targets of DAF-18 protein- phosphatase activity, identification of transcriptional effector mechanisms of DAF-18 and LIN-35, identification of novel regulators of starvation resistance, anatomical resolution of the starvation response, elucidation of regulatory interactions among signaling pathways affecting starvation-induced tumor formation, and molecular mechanisms governing lipoprotein trafficking. The lab will leverage their expertise in rigorous genetic analysis, innovative functional genomics, mechanistic biochemistry, and automated image analysis. Closing these gaps will be significant given conservation of critical disease-relevant function of the potent regulators involved.